Substituted indazole-O-glucosides

ABSTRACT

Substituted indazole-O-glucosides, compositions containing them, and methods of using them, for example for the treatment of diabetes and Syndrome X are disclosed.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit of provisional applications Ser. No.60/579,722, filed 15 Jun. 2004; Ser. No. 60/519,381, filed 12 Nov. 2003;Ser. No. 60/491,523, filed 1 Aug. 2003; and Ser. No. 60/491,534, filed 1Aug. 2003, each of which is incorporated by reference herein.

FIELD OF THE INVENTION

This invention relates to substituted indazole-O-glucosides,compositions containing them, and methods of using them, for example,for the treatment or prophylaxis of diabetes and Syndrome X.

BACKGROUND OF THE INVENTION

Diabetes is a chronic disorder affecting carbohydrate, fat and proteinmetabolism in animals.

Type I diabetes mellitus, which comprises approximately 10% of alldiabetes cases, was previously referred to as insulin-dependent diabetesmellitus (“IDDM”) or juvenile-onset diabetes. This disease ischaracterized by a progressive loss of insulin secretory function bybeta cells of the pancreas. This characteristic is also shared bynon-idiopathic, or “secondary”, diabetes having its origins inpancreatic disease. Type I diabetes mellitus is associated with thefollowing clinical signs or symptoms: persistently elevated plasmaglucose concentration or hyperglycemia; polyuria; polydipsia and/orhyperphagia; chronic microvascular complications such as retinopathy,nephropathy and neuropathy; and macrovascular complications such ashyperlipidemia and hypertension which can lead to blindness, end-stagerenal disease, limb amputation and myocardial infarction.

Type II diabetes mellitus (non-insulin-dependent diabetes mellitus orNIDDM) is a metabolic disorder involving the dysregulation of glucosemetabolism and impaired insulin sensitivity. Type II diabetes mellitususually develops in adulthood and is associated with the body'sinability to utilize or make sufficient insulin. In addition to theinsulin resistance observed in the target tissues, patients sufferingfrom type II diabetes mellitus have a relative insulin deficiency—thatis, patients have lower than predicted insulin levels for a given plasmaglucose concentration. Type II diabetes mellitus is characterized by thefollowing clinical signs or symptoms: persistently elevated plasmaglucose concentration or hyperglycemia; polyuria; polydipsia and/orhyperphagia; chronic microvascular complications such as retinopathy,nephropathy and neuropathy; and macrovascular complications such ashyperlipidemia and hypertension which can lead to blindness, end-stagerenal disease, limb amputation and myocardial infarction.

Syndrome X, also termed Insulin Resistance Syndrome (IRS), MetabolicSyndrome, or Metabolic Syndrome X, is recognized in some 2% ofdiagnostic coronary catheterizations. Often disabling, it presentssymptoms or risk factors for the development of Type II diabetesmellitus and cardiovascular disease, including impaired glucosetolerance (IGT), impaired fasting glucose (IFG), hyperinsulinemia,insulin resistance, dyslipidemia (e.g., high triglycerides, low HDL),hypertension and obesity.

Therapy for IDDM patients has consistently focused on administration ofexogenous insulin, which may be derived from various sources (e.g.,human, bovine, porcine insulin). The use of heterologous speciesmaterial gives rise to formation of anti-insulin antibodies which haveactivity-limiting effects and result in progressive requirements forlarger doses in order to achieve desired hypoglycemic effects.

Typical treatment of Type II diabetes mellitus focuses on maintainingthe blood glucose level as near to normal as possible with lifestylemodification relating to diet and exercise, and when necessary, thetreatment with anti-diabetic agents, insulin or a combination thereof.NIDDM that cannot be controlled by dietary management is treated withoral antidiabetic agents.

Although insulin resistance is not always treated in all Syndrome Xpatients, those who exhibit a prediabetic state (e.g., IGT, IFG), wherefasting glucose levels may be higher than normal but not at the diabetesdiagnostic criterion, is treated in some countries (e.g., Germany) withmefformin to prevent diabetes. The anti-diabetic agents may be combinedwith pharmacological agents for the treatment of the concomitantco-morbidities (e.g., antihypertensives for hypertension, hypolipidemicagents for lipidemia).

First-line therapies typically include metformin and sulfonylureas aswell as thiazolidinediones. Mefformin monotherapy is a first linechoice, particularly for treating type II diabetic patients who are alsoobese and/or dyslipidemic. Lack of an appropriate response to mefforminis often followed by treatment with metformin in combination withsulfonylureas, thiazolidinediones, or insulin. Sulfonylurea monotherapy(including all generations of drugs) is also a common first linetreatment option. Another first line therapy choice may bethiazolidinediones. Alpha glucosidase inhibitors are also used as firstand second line therapies. Patients who do not respond appropriately tooral anti-diabetic monotherapy, are given combinations of theabove-mentioned agents. When glycemic control cannot be maintained withoral antidiabetics alone, insulin therapy is used either as amonotherapy, or in combination with oral antidiabetic agents.

One recent development in treating hyperglycemia is focused on excretionof excessive glucose directly into urine. Specific inhibitors of SGLTshave been shown to increase the excretion of glucose in urine and lowerblood glucose levels in rodent models of IDDM and NIDDM.

SUMMARY OF THE INVENTION

One aspect of the present invention is directed to compounds, methodsand compositions for the treatment or prophylaxis of diabetes, SyndromeX, or associated symptoms or complications. More specifically, thisinvention is directed to a method of treating diabetes or Syndrome X, orassociated symptoms or complications thereof, in a subject afflictedwith such a condition, said method comprising the step of administeringone or more glucose reabsorption inhibitors disclosed herein. Accordingto one aspect of the invention, said method of treatment can furthercomprise the step of administering one or more additional antidiabeticagents, such as a second antidiabetic agent or a second and a thirdantidiabetic agent.

Another aspect of the invention features a compound of formula(II):

wherein

-   R¹ is H or C₁₋₄ alkyl;-   R² is H, F, Cl, methoxy, or C₁₋₃ alkyl;-   Q is —(CH₂)_(n)— where n is 0, 1, or 2; or, where R² is H, F, Cl, or    methoxy, then Q can also be selected from —CH₂—S;-   Z is substituted or unsubstituted, and is selected from C₃₋₇    cycloalkyl, phenyl, benzhydryl, a 5- or 6-membered heteroaryl having    1 or 2 heteroatoms independently selected from N, O, and S, a    biaryl, a 9- or 10-membered fused bicyclyl (such as naphthyl), and a    fused heterobicyclyl, wherein said fused heterobicyclyl has between    1 and 4 heteroatoms (and preferably between 1 and 3 or between 1 and    2 heteroatoms) independently selected from N, O, and S;-   P═H or acetyl;    or a pharmaceutically acceptable salt, amide, or ester thereof.

One aspect of the invention features a pharmaceutical compositioncomprising a glucose reabsorption inhibitor, at least one additionalanti-diabetic agent (such as one, two, three additional anti-diabeticagents), and a pharmaceutically acceptable carrier. The invention alsoprovides a process for formulating a pharmaceutical composition,comprising formulating together a glucose reabsorption inhibitor, asecond anti-diabetic agent, and a pharmaceutically acceptable carrier.

An embodiment of the invention is a method for treating diabetes orSyndrome X, or associated symptoms or complications thereof in asubject, said method comprising administering to said subject a jointlyeffective amount of a glucose reabsorption inhibitor and administeringto said subject a jointly effective amount of a second anti-diabeticagent, said combined administration providing the desired therapeuticeffect.

Another embodiment of the invention is a method for inhibiting the onsetof diabetes or Syndrome X, or associated symptoms or complicationsthereof in a subject, said method comprising administering to saidsubject a jointly effective dose of a glucose reabsorption inhibitor andadministering to said subject a jointly effective amount of an secondanti-diabetic agent, said combined administration providing the desiredprophylactic effect.

In the disclosed methods, the diabetes or Syndrome X, or associatedsymptoms or complications thereof, is selected from IDDM, NIDDM, IGT,IFG, obesity, nephropathy, neuropathy, retinopathy, atherosclerosis,polycystic ovarian syndrome, hypertension, ischemia, stroke, heartdisease, irritable bowel disorder, inflammation, and cataracts.

Also included in the invention is the use of one or more glucosereabsorption inhibitors in combination with one or more anti-diabeticagents for the preparation of a medicament for treating a conditionselected from IDDM, NIDDM, IGT, IFG, obesity, nephropathy, neuropathy,retinopathy, atherosclerosis, polycystic ovarian syndrome, hypertension,ischemia, stroke, heart disease, irritable bowel disorder, inflammation,and cataracts.

DETAILED DESCRIPTION OF THE INVENTION

All diabetics, regardless of their genetic and environmentalbackgrounds, have in common an apparent lack of insulin or inadequateinsulin function. Because transfer of glucose from the blood into muscleand fatty tissue is insulin dependent, diabetics lack the ability toutilize glucose adequately, which leads to undesired accumulation ofglucose in the blood (hyperglycemia). Chronic hyperglycemia leads todecrease in insulin secretion and contributes to increased insulinresistance, and as a result, the blood glucose concentration isincreased so that diabetes is self-exacerbated (Diabetologia, 1985,“Hyperglycaemia as an inducer as well as a consequence of impaired islecell function and insulin resistance: implications for the management ofdiabetes”, Vol. 28, p.119); Diabetes Cares, 1990, Vol.13, No. 6,“Glucose Toxicity”, pp. 610–630). Therefore, by treating hyperglycemia,the aforementioned self-exacerbating cycle is interrupted so that theprophylaxis or treatment of diabetes is made possible.

U.S. Pat. No. 6,153,632 to R. Rieveley discloses a method andcomposition stated to be for the treatment of diabetes mellitus (Type I,Impaired Glucose Tolerance [“IGT”] and Type II), which incorporates atherapeutic amount of one or more insulin sensitizers along with one ormore of an orally ingested insulin, an injected insulin, a sulfonylurea,a biguanide or an alpha-glucosidase inhibitor for the treatment ofdiabetes mellitus.

According to one aspect, the invention features the combination of aPPAR modulator, preferably a PPAR δ agonist, and an SGLT inhibitor,preferably an SGLT 2 inhibitor or a selective SGLT 2 inhibitor.

A. Terms

Some terms are defined below and by their usage throughout thisdisclosure.

Unless otherwise noted, “alkyl” and “alkoxy” as used herein, whetherused alone or as part of a substituent group, include straight, cyclic,and branched-chain alkyl having 1 to 8 carbon atoms, or any numberwithin this range. For example, alkyl radicals include methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, 2-butenyl,2-butynyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl,neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals areoxygen ethers formed from the previously described straight or branchedchain alkyl groups. The alkyl and alkoxy group may be independentlysubstituted with one to five, preferably one to three groups selectedfrom halogen (F, Cl, Br, I), oxo, OH, amino, carboxyl, and alkoxy. Thealkyl and alkoxy group may also be independently linked to one or morePEG radicals (polyethylene glycol).

The term “acyl” as used herein, whether used alone or as part of asubstituent group, means an organic radical having a carbonyl grouplinked to hydrocarbyl group having 1 to 7 carbon atoms (branched orstraight chain or cyclic) derived from an organic acid by removal of thehydroxyl group. For example C₄ acyl can include (CO)CH₂CH₂CH₂CH₃ and(CO)(CH₂(CH)(CH₃)₂; similarly, C₆ acyl includes both (CO)(C₆H₁₃) and(CO)(C₆H₅). The term “Ac” as used herein, whether used alone or as partof a substituent group, means acetyl.

“Aryl” is a carbocyclic aromatic radical including, but not limited to,phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radicalmay be substituted by independent replacement of 1 to 3 of the hydrogenatoms thereon with halogen, OH, CN, mercapto, nitro, amino, cyano,optionally substituted C₁–C₈-alkyl, optionally substituted alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-amino,di(C₁–C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—. Illustrative aryl radicals include, for example, phenyl,naphthyl, biphenyl, indene

indane

fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl,carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl,hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl,acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. “Ph”or “PH” denotes phenyl.

The term “heteroaryl” as used herein represents a stable five orsix-membered monocyclic or bicyclic aromatic ring system which consistsof carbon atoms and from one to three heteroatoms selected from N, O andS. The heteroaryl group may be attached at any heteroatom or carbonatom, which results in the creation of a stable structure. Examples ofheteroaryl groups include, but are not limited to benzofuranyl,benzothiophenyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl,thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl,pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl,benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl,benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl,benzotriazolyl or quinolinyl. Prefered heteroaryl groups includepyridinyl, thiophenyl, furanyl, and quinolinyl. When the heteroarylgroup is substituted, the heteroaryl group may have one to threesubstituents which are independently selected from halogen, OH, CN,mercapto, nitro, amino, cyano, optionally substituted C₁–C₈-alkyl,optionally substituted alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl,alkyl-amino, di(C₁–C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—.

The terms “heterocycle,” “heterocyclic,” and “heterocyclyl” refer to anoptionally substituted, fully or partially saturated, aromatic ornonaromatic, cyclic group which is, for example, a 4- to 7-memberedmonocyclic, 7- to 11-membered bicyclic (“heterobicyclyl”) (such as 9–10bicyclic), or 10- to 15-membered tricyclic ring system, which has atleast one heteroatom in at least one carbon atom containing ring. Eachring of the heterocyclic group containing a heteroatom may have 1, 2, or3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfuratoms, where the nitrogen and sulfur heteroatoms may also optionally beoxidized. The nitrogen atoms may optionally be quaternized. Theheterocyclic group may be attached at any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl;pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl;isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl;piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl;2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl;tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl;thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone;1,3-dioxolane; dioxanyl; thietanyl, thiiranyl; and the like. Exemplaryheterobicyclyl groups include quinuclidinyl; tetrahydroisoquinolinyl;dihydroisoindolyl; dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl;dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone;dihydrobenzopyranyl; indolinyl; isochromanyl; isoindolinyl; piperonyl;tetrahydroquinolinyl; benzimidazolyl; benzthiazolyl; and the like. Whenthe heteroaryl group is substituted, the heterocyclyl may beindependently substituted with one to five, preferably one to threegroups selected from halogen, OH, CN, mercapto, nitro, amino, cyano,optionally substituted C₁–C₈-alkyl, optionally substituted alkoxy,alkylthio, alkylsulfinyl, alkylsulfonyl, alkyl-amino,di(C₁–C₈-alkyl)amino, formyl, carboxyl, alkoxycarbonyl,alkoxycarbonyloxy, alkanoyloxy, phenyl, carbamoyl, carboxamide, di-loweralkylcarbamoyloxy, phenoxycarbonyloxy group, lower alkylenedioxy,benzoyloxy, alkyl-CO—O—, alkyl-O—CO—, —CONH₂, alkyl-O—CO—O—, oralkyl-CO—NH—.

The term “biaryl” includes a heteroaryl linked to a phenyl, a phenyllinked to a heteroaryl (such as furan, pyridine, thiophene), and aphenyl linked to a phenyl. Examples of phenyl-phenyl, heteroaryl-phenyl,substituted heteroaryl-phenyl, and phenyl-heteroaryl, respectively,include:

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combinations of thespecified ingredients in the specified amounts.

The term “combined administration” includes co-administrationwherein: 1) the two or more agents are administered to a subject atsubstantially similar times; and 2) the two or more agents areadministered to a subject at different times, at independent intervalswhich may or may not overlap or coincide.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who is the object of treatment,observation or experiment.

The term “RXR modulator” as used herein, refers to Retinoid-X receptoragonists, partial agonists, or antagonists. Preferably the modulatorincreases insulin sensitivity. According to one aspect, the modulator isan RXR agonist.

Diabetes, Syndrome X, and associated symptoms or complications includesuch conditions as IDDM, NIDDM, IGT, IFG, obesity, nephropathy,neuropathy, retinopathy, atherosclerosis, polycystic ovarian syndrome,hypertension, ischemia, stroke, heart disease, irritable bowel disorder,inflammation, and cataracts. Examples of a prediabetic state includesIGT and IFG.

Methods are known in the art for determining effective doses fortherapeutic and prophylactic purposes for the disclosed pharmaceuticalcompositions or the disclosed drug combinations, whether or notformulated in the same composition. For therapeutic purposes, the term“jointly effective amount” as used herein, means that amount of eachactive compound or pharmaceutical agent, alone or in combination, thatelicits the biological or medicinal response in a tissue system, animalor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes alleviation of the symptoms ofthe disease or disorder being treated. For prophylactic purposes (i.e.,inhibiting the onset or progression of a disorder), the term “jointlyeffective amount” refers to that amount of each active compound orpharmaceutical agent, alone or in combination, that inhibits in asubject the onset or progression of a disorder as being sought by aresearcher, veterinarian, medical doctor or other clinician, thedelaying of which disorder is mediated by the modulation of glucosereabsorption activity or other antidiabetic activity or both. Thus, thepresent invention provides combinations of two or more drugs wherein,for example, (a) each drug is administered in an independentlytherapeutically or prophylactically effective amount; (b) at least onedrug in the combination is administered in an amount that issub-therapeutic or sub-prophylactic if administered alone, but istherapeutic or prophylactic when administered in combination with thesecond or additional drugs according to the invention; or (c) both drugsare administered in an amount that is sub-therapeutic orsub-prophylactic if administered alone, but are therapeutic orprophylactic when administered together.

The term “protecting groups” refer to those moieties known in the artthat are used to mask functional groups; protecting groups may beremoved during subsequent synthetic transformations or by metabolic orother in vivo administration conditions. During any of the processes forpreparation of the compounds of the present invention, it may benecessary and/or desirable to protect sensitive or reactive groups onany of the molecules concerned. This may be achieved by means ofconventional protecting groups, such as those described in ProtectiveGroups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973;and T. W. Greene & P. G. M. Wuts, Protective Groups in OrganicSynthesis, Third Edition, John Wiley & Sons, 1999. The protecting groupsmay be removed at a convenient subsequent stage using methods known inthe art. Examples of hydroxyl and diol protecting groups are providedbelow.

Protection for the hydroxyl group includes methyl ethers, substitutedmethyl ethers, substituted ethyl ethers, substitute benzyl ethers, andsilyl ethers.

Substituted Methyl Ethers

Examples of substituted methyl ethers include methyoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,guaiacolmethyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl,2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl,1-methoxycyclohexyl, 4-methoxytetrahydropyranyl,4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranylS,S-dioxido, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl,1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl and2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl.

Substituted Ethyl Ethers

Examples of substituted ethyl ethers include 1-ethoxyethyl,1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl,t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl,benzyl, and polyethyleneglycol ethers.

Substituted Benzyl Ethers

Examples of substituted benzyl ethers include p-methoxybenzyl,3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl,3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl,5-dibenzosuberyl, triphenylmethyl, α-naphthyidiphenylmethyl,p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl,tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxy)phenyldiphenylmethyl,4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl,4,4′,4″-tris(levulinoyloxyphenyl)methyl,4,4′,4″-tris(benzoyloxyphenyl)methyl,3-(Imidazol-1-ylmethyl)bis(4′,4-dimethoxyphenyl)methyl,1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl,9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,1,3-benzodithiolan-2-yl, and benzisothiazolyl S,S-dioxido.

Silyl Ethers

Examples of silyl ethers include trimethylsilyl, triethylsilyl,triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl,dimethylthexylsilyl, t-butyldimethylsilyl, t-butyidiphenylsilyl,tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl,and t-butylmethoxyphenylsilyl.

Esters

In addition to ethers, a hydroxyl group may be protected as an ester.Examples of esters include formate, benzoylformate, acetate,chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate,methoxyacetate, triphenylmethoxyacetate, phenoxyacetate,p-chlorophenoxyacetate, p-P-phenylacetate, 3-phenylpropionate,4-oxopentanoate(levulinate), 4,4-(ethylenedithio)pentanoate, pivaloate,adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate,2,4,6-trimethylbenzoate(mesitoate), and polyethyleneglycol esters.

Carbonates

Examples of carbonates include methyl, 9-fluorenylmethyl, ethyl,2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl,2-(triphenylphosphonio)ethyl, isobutyl, vinyl, allyl, p-nitrophenyl,benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl,p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, methyldithiocarbonate, and polyethyleneglycol carbonates.

Assisted Cleavage

Examples of assisted cleavage include 2-iodobenzoate, 4-azidobutyrate,4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl carbonate,4-(methylthiomethoxy)butyrate, and 2-(methylthiomethoxymethyl)benzoate.

Miscellaneous Esters

Examples of miscellaneous esters include2,6-dichloro-4-methylphenoxyacetate,2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate(tigloate),o-(methoxycarbonyl)benzoate, p-P-benzoate, α-naphthoate, nitrate, alkylN,N,N′,N′-tetramethylphosphorodiamidate, N-phenylcarbamate, borate,dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate

Sulfonates

Examples of sulfonates include sulfate, methanesulfonate(mesylate),benzylsulfonate, and tosylate.

Protection for 1,2- and 1,3-Diols

Cyclic Acetals and Ketals

Examples of cyclic acetals and ketals include methylene, ethylidene,1-t-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl)ethylidene,2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene,cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene,2,4-dimethoxybenzylidene, 3,4-dimethoxybenzylidene, and2-nitrobenzylidene.

Cyclic Ortho Esters

Examples of cyclic ortho esters include methoxymethylene,ethoxymethylene, dimethoxymethylene, 1-methoxyethylidene,1-ethoxyethylidine, 1,2-dimethoxyethylidene, α-methoxybenzylidene,1-(N,N-dimethylamino)ethylidene derivative,α-(N,N-dimethylamino)benzylidene derivative, and 2-oxacyclopentylidene.

Silyl Derivatives

Examples of silyl derivatives include di-t-butylsilylene group, and1,3-(1,1,3,3-tetraisopropyldisiloxanylidene) derivative.

Glucose Reabsorption Inhibitors

One method of treating hyperglycemia is to excrete excessive glucosedirectly into urine so that the blood glucose concentration isnormalized. For example, sodium-glucose cotransporters (SGLTs),primarily found in chorionic membrane of the intestine and the kidney,are a family of proteins actively involved in the normal process ofglucose absorption. Among them, SGLT1 is present in intestinal and renalepithelial cells (Lee et al., 1994), whereas SGLT2 is found in theepithelium of the kidney (You et al., 1995, MacKenzie et al., 1994).Glucose absorption in the intestine is primarily mediated by SGLT1, ahigh-affinity low-capacity transporter with a Na⁺:glucose transportratio of 2:1. SGLT2, also known as SAAT1, transports Na⁺ and glucose ata ratio of 1:1 and functions as a low-affinity high-capacitytransporter. These SGLTs are characterized in Table 1:

TABLE 1 Preferred K_(m)* TmG** K_(m)* ISOFORM TISSUE StoichiometrySubstrate in vitro in vitro In vivo SGLT1 Sm. Intestine 2:1 D-glucose0.1 nd Nd D-galactose Kidney (S1, S3) 2:1 D-glucose 0.39 7.9 0.3D-galactose SGLT2 Kidney (S3) 1:1 D-glucose 1.64 83 6 (SAAT1) *(mM) forD-glucose **Maximal transport rate pmol/min/mm

Renal reabsorption of glucose is mediated by SGLT1 and SGLT2 (Silvermanet al., 1992; Deetjen et al., 1995). Plasma glucose is filtered in theglomerulus and is transepithelially reabsorbed in the proximal tubules.SGLT1 and SGLT2 are located in the apical plasma membranes of theepithelium and derive their energy from the inward sodium gradientcreated by the Na⁺/K⁺ ATPase pumps located on the basolateral membrane.Once reabsorbed, the elevated cytosolic glucose is then transported tothe interstitial space by facilitated glucose transports (GLUT1 andGLUT2). Therefore, inhibition of SGLTs reduces plasma glucose throughsuppression of glucose reabsorption in the kidney. A therapeutically orprophylactically effective amount of an SGLT inhibitor, such as thatsufficient to increase urine glucose excretion, or to decrease plasmaglucose, in a subject by a desired amount per day, can be readilydetermined using methods established in the art. Recently, it has beenfound that phlorizin, a natural glycoside present in barks and stems ofRosaceae (e.g., apple, pear, etc.), inhibits Na⁺-glucose co-transporterslocated in chorionic membrane of the intestine and the kidney. Byinhibiting Na⁺-glucose co-transporter activity, phlorizin inhibits therenal tubular glucose reabsorption and promotes the excretion of glucoseso that the glucose level in a plasma is controlled at a normal levelfor a long time via subcutaneous daily administration (Journal ofClinical Investigation, 1987, Vol. 79, p. 1510).

Other SGLT inhibitors include alkyl- and phenyl-glucosides,1-5-isoquinolinesulfonyl)-2-methylpiperazine-HCl (indirectly via proteinkinase C), p-chloromercuribenzoate (PCMB), N,N′-dicyclohexylcarbodiimide(DCCD), copper and cadmium ions, and trivalent lanthanides.

B. Compounds

The invention features compounds of Formula (II):

wherein

-   R¹ is H or C₁₋₄ alkyl;-   R² is H, F, Cl, methoxy, or C₁₋₃ alkyl;-   Q is —(CH₂)_(n)— where n=0, 1, or 2; or, where R² is H, F, Cl, or    methoxy, then Q can also be selected from —CH₂—S;-   P═H or acetyl;-   Z is substituted or unsubstituted, and is selected from C₃₋₇    cycloalkyl, phenyl, benzhydryl, 5- or 6-membered heteroaryl having 1    or 2 heteroatoms independently selected from N, O, and S, a biaryl,    a 9- or 10-membered fused bicyclyl or fused heterobicyclyl, wherein    each fused heterobicyclyl has between 1 and 4 heteroatoms (and    preferably between 1 and 2 heteroatoms) independently selected from    N, O, and S.

Examples of preferred compounds of Formula(II) include:

-   (a) R¹ is H; (b) R² is H, methyl, or ethyl; (c) Q is —(CH₂)_(n)— and    n is 1 or 2; (d) Z is independently substituted with between 1 and 3    substituents independently selected from C₁₋₄ alkoxy, C₁₋₄ alkyl,    C₃₋₆ cycloalkyl, halo, hydroxy, cyano, amino, C₁₋₄ alkylthio, C₁₋₄    aminoalkyl, mono- or dialkylamino, phenyl, 5–6 membered heterocyclyl    containing between 1 and 3 heteroatoms independently selected from    N, S, and O; and wherein the substituent(s) on Z can be further    independently substituted with between 1 and 3 substitutents    independently selected from C₁₋₄ alkoxy, C₁₋₄ alkyl, halo, hydroxy,    cyano, amino, C₁₋₄ alkylthio phenoxy, —CONR^(a)R^(b), —NHSO₂R^(a),    and —SO₂NR^(a)R^(b); (e) Z is phenyl, cyclopentyl, cyclohexyl,    4-substituted cyclohexyl, 2- or 3-substituted cyclopentyl,    4-substituted phenyl, 3,4-disubstituted phenyl, substituted    thiophene, thiophenyl, benzofuranyl, dihydrobenzofuranyl,    4-substituted pyridyl, benzo[b]thienyl, chromanyl, benzothiophenyl,    indanyl, naphthyl, 5,6,7,8-tetrahydronapthyl,    1,2,3,4-tetrahydronaphthyl, or benzo[1,4] dioxan; (f) limitations    of (e) wherein Z is unsubstituted or substituted with between 1 and    2 substituents independently selected from methoxy, ethoxy, fluoro,    chloro, methyl, ethyl, propyl, isopropyl, cyclopropyl, and    phenyl; (g) Z is biphenyl, 4-ethylphenyl, (4-propyl)phenyl,    4-methoxyphenyl, 4-ethoxyphenyl, 4-methylthiophenyl,    benzofuran-5-yl, dihydrobenzofuran-5-yl, naphthyl, or    dihydrobenzofuran-6-yl, or (5-ethylthio)phenyl; (h) R¹ is H; and R²    is H, methyl, ethyl, propyl, or isopropyl; (i) Q is —(CH₂)_(n)—; n    is 1 or 2; and R² is H, methyl, or ethyl; (i) limitation of (i)    wherein R¹ is methyl; (j) limitation of (a) wherein R² is H, methyl,    or ethyl; and Q is —(CH₂)_(n)— and n is 1 or 2; Z is phenyl,    cyclopentyl, cyclohexyl, 4-substituted cyclohexyl, 2- or    3-substituted cyclopentyl, 4-substituted phenyl, 3,4-disubstituted    phenyl, substituted thiophene, thiophenyl, biaryl, benzofuranyl,    dihydrobenzofuranyl, 4-substituted pyridyl, benzo[b]thienyl,    benzothiophenyl, indanyl, naphthyl, 5,6,7,8-tetrahydronapthyl,    1,2,3,4-tetrahydronaphthyl, or benzo[1,4] dioxan; and wherein Z is    unsubstituted or substituted with between 1 and 2 substituents    independently selected from methoxy, ethoxy, fluoro, chloro, methyl,    ethyl, propyl, isopropyl, cyclopropyl, phenyl; (k) R² is H, methyl,    or ethyl; wherein Q is —(CH₂)_(n)— and n is 1 or 2; and Z is    biphenyl, 4-ethylphenyl, (4-propyl)phenyl, 4-methoxyphenyl,    4-ethoxyphenyl, 4-methylthiophenyl, benzofuran-5-yl,    dihydrobenzofuran-5-yl, naphthyl, or dihydrobenzofuran-6-yl, or    (5-ethylthio)phenyl; (I) and combinations of the above.

Examples of preferred compounds include:2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-[3-(2-Benzofuran-5-yl-ethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1,6-dimethyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-ethyl-1H-indazol-4-yloxy}-β-D-glucopyranosideand2-[3-(4-Methoxy-benzyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside.

Additional preferred compounds include:2-[3-(2-Benzofuran-5-yl-ethyl)-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(6-Methoxy-naphthalen-2-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(4-Ethoxy-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-{6-Methyl-3-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-[6-Methyl-3-(2-naphthalen-2-yl-ethyl)-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(4-Methoxy-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}β-D-glucopyranoside;2-{3-[2-(6-Methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}β-D-glucopyranoside and2-[3-(2-Benzofuran-5-yl-ethyl)-6-methyl-1H-indazol-4-yloxy]-6-O-acetyl-β-D-glucopyranoside.

Additional preferred compounds include:2-{3-[2-(6-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(4-Chloro-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}p-D-glucopyranoside;2-[3-(4-Methoxy-phenylsulfanylmethyl)-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[3-(2-Cyclohexyl-ethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(4-Trifluoromethyl-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(4-Methanesulfonylamino-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranosideand2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-6-O-acetyl-β-D-glucopyranoside.

Additional preferred compounds include2-[3-(4-Ethyl-benzyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[6-Methyl-3-(4-propyl-benzyl)-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Methylsulfanyl-benzyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Biphenyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Cyclopropyl-benzyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranosideand2-[3-(5-Ethylthiophen-2-ylmethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside.

The most preferred compounds are2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-[3-(2-Benzofuran-5-yl-ethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranosideand2-[3-(5-Ethylthiophen-2-ylmethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside.

C. Synthetic Methods

One aspect of the invention features substituted indazoles of Formula(II). These compounds can be prepared according to traditional syntheticorganic chemistry methods or according to combinatorial or matrixsynthesis methods. The following three Schemes, narrative, and chemistryExamples 1–22 provide general guidance.

Compounds of this invention, wherein R₂ is as defined in Formula (II)and Z is an aromatic or a cycloalkyl ring, can be prepared as outlinedin Schemes 1 and 3. As set forth in Scheme 1, compounds of Formula 1 areeither commercially available (wherein R₂ is H, methyl or methoxy) orcan be prepared by literature methods [when R₂ is chloro, ethyl, propyl,isopropyl: Tsujihara et al. J. Med. Chem. 1999 42, 5311–5324; when R₂ isfluoro: Brooks et al. J. Org. Chem. 1999, 64, 9719–9721] fromcommercially available materials. Compounds of Formula 2 wherein n is 0or 1 can be prepared from compounds 1 by Friedel-Crafts acylation withan aryl acid chloride or an arylacetic acid using a Lewis acid, such asboron trifluoride diethyl etherate under neat conditions.

Compounds of Formula 3, where P₁ is benzyl (Bn) or methoxymethyl (MOM),can be prepared from compounds of Formula 1 by literature methods[Tsujihara et al. J. Med. Chem. 1999 42, 5311–5324]. Compounds ofFormula 2 where n is 2 can be prepared from compounds of Formula 3 ineither two or three steps. Aldol condensation with an aryl aldehydeunder basic conditions, such as a potassium hydroxide, in an alcoholicsolvent such as ethanol at temperatures from 20° C. to reflux, followedby catalytic hydrogenation of the resulting alkene under conditions suchas Pd on charcoal in an alcoholic solvent such as ethanol under hydrogenpressure from 1–3 atmospheres. When P₁ is benzyl, the groups are cleavedduring hydrogenation to yield compounds of Formula 2 directly. When P₁is MOM, the intermediate from catalytic hydrogenation is treated with amineral acid such as hydrochloric acid in a combination of solvents suchas dioxane and isopropyl alcohol.

Alternatively compounds of Formula 3, where P₁ is benzyl, can be treatedwith a strong base such as lithium diisopropylamide at −78° C., followedby the addition of cycloalkyl carboxaldehyde at −30° C. The product isthen hydrogenated to simultaneously reduce the double bonds and removethe phenol-protecting group, thereby providing compounds of Formula 2wherein n is 2, and Z is cycloalkyl.

Compounds of Formula 4 where R₁ is H or methyl can be prepared bycyclization of compounds of Formula 2 with hydrazine or methylhydrazinein an alcoholic solvent such as ethylene glycol at temperatures rangingfrom 140° C. to 160° C. Alternatively, a compound of Formula 4 where R₁is alkyl can be obtained in three steps from a compound of Formula 4where R₁ is H.

The phenol group in a compound of Formula 4, where R₁ is H, can beselectively alkylated with benzyl bromide in a polar solvent such asacetone in the presence of a base such as potassium carbonate. Theresulting indazole can be alkylated with an alkyl iodide, such as ethyliodide, and a base such as cesium carbonate in DMF or some other polarorganic solvent.

Deprotection of the phenol group under hydrogenation conditions, such aspalladium on charcoal and hydrogen gas at pressures ranging from 1 to 3atmospheres in a solvent such as methanol, ethanol, ethyl acetate andthe like, will provide compounds of Formula 4 where R₁ is an alkylgroup, such as ethyl.

Compounds of this invention where R₂ is as defined in Formula (II), andZ is an aromatic ring, can be prepared as outlined in Schemes 2 and 3.Compounds of Formula 5 can be obtained from commercial sources orprepared by literature methods [Tsujihara et al. J. Med. Chem. 1999 42,5311–5324]. A compound of Formula 6 can be prepared from a compound ofFormula 5 by cyclization with hydrazine in an alcoholic solvent such asethylene glycol at temperatures ranging from 140° C. to 160° C. Stepwiseprotection of a compound of Formula 6 provides a compound of Formula 7.Protection of the phenol can be accomplished with an ether-formingreagent such as tert-butyldimethylsilyl chloride and an amine such asimidazole in a polar solvent such as DMF, at temperature ranging from 0°C. to 80° C. Protection of the indazole nitrogen with a reagent such asdi-tert-butyl dicarbonate in a solvent such as THF provides a compoundof Formula 7 where P₁ is tert-butyldimethylsilyl and P₂ ist-butoxycarbonyl (BOC). The indazole nitrogen can also be protected withan acylating agent such as acetic anhydride, with or without a catalystsuch as DMAP in a nonpolar solvent such as methylene chloride to yield acompound of Formula 7 where P₂ is acetyl (Ac). Subsequent brominationwith a reagent such as N-bromosuccinimide (NBS) in the presence of acatalytic amount of benzoyl peroxide or 2,2′-azobisisobutyronitrile(AlBN) in a solvent such as carbon tetrachloride can provide compoundsof Formula 8. A compound of formula 9 can then be obtained by reactionwith an appropriately substituted thiophenol using a base such astriethylamine in a nonpolar solvent such as dichloromethane attemperatures ranging from 0° C.–50° C. The protecting groups P₁ (TBDMS)and P₂ (BOC) in a compound of Formula 9 can be removed simultaneouslyunder acidic conditions such as aqueous HBr in a polar solvent such asDMF with potassium fluoride at room temperature to provide a compound ofFormula 10. The acetyl (Ac) group P₂ of a compound of Formula 11 can beremoved after glycosylation as described in Scheme 3.

Compounds of Formula 12, where R₁ is as defined in Formula II, can beobtained from compounds of Formula 4, 10 and 11, prepared in Schemes 1and 2, by glycosidation of the phenol group with2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in an appropriatesolvent, such as acetone, acetonitrile or DMF under basic conditions,such as potassium carbonate or lithium carbonate, followed bydeprotection of acetyl groups in an alcoholic solvent such as methanolusing mild basic conditions such as potassium carbonate or sodiummethoxide at room temperature. A compound of Formula 13 can be isolatedas a by-product in the deprotection step.

D. Additional Antidiabetic Agents

Antidiabetic agents that can be used, according to aspects of theinvention, as a second or a third antidiabetic agent in a pharmaceuticalcomposition, a formulation, or a combination method of treatment(treatment regimen) include, but are not limited to, the classes ofcompounds exemplified in Table 2.

TABLE 2 Combination Therapies with SGLT Inhibitors Mechanism or ClassDrug/Compound Biguanide (class) metformin Fortamet (metformin XT)metformin GR metformin XL NN-414 fenofibrate/metformin combo InsulinSecretagogue glimeparide (mech), Sulfonylureas (class)glyburide/glibenclamide combo glyburide/metformin combo glipizideglipizide/metformin combo gliclazide chlorpropamide tolbutamidetolazamide Insulin Secretagogue repaglinide (mech), Meglitinides (class)nateglinide mitiglinide Alpha-glucosidase acarbose inhibitors (mech)miglitol voglibose emiglitate Insulin and Insulin insulin lisproanalogues (class) insulin glargine insulin detemir insulin glulisineinsulin aspart human insulin (Humulin R) human insulin (Novolin R humaninsulin (Novolin BR) insulin, zinc suspension (Humulin L) insulin NHP(Humulin N) insulin, zinc suspension (Novolin L) insulin NHP (Novolin N)insulin, zinc suspension (Humulin U) human insulin, regular and NHP mix(Humulin 50/50) human insulin, regular and NHP mix (Humulin 70/30) humaninsulin, regular and NHP mix (Novolin 70/30) Inhaled insulin (class)Exubera AERx Insulin Diabetes Management System AIR inhaled insulin Oralinsulin (class) Oralin PPARgamma (mech) rosiglitazonerosiglitazone/metformin combo pioglitazone isaglitazone (netoglitazone,MCC-555) rosiglitazone/sulfonylurea ragaglitazar balaglitazone (NN-2344)R-483 rivoglitazone (CS-011) FK-614 SCD-DKY tesaglitazar T131 CLX0921LY-293111 (VML-295) MBX 102 AA10090 CDDO (TP-155C) DRF-2189 PHT-46farglitazar GW-7845 L-764406 NC-2100 PN 2022 (PN 2034) PPARalpha/gammadual MK767/MK0767 (KRP 297) agonists (mech) muraglitazar (BMS-298585)tesaglitazar LY-818 oxeglitazar (EML-4156) LY-929 BVT-142 DRF-2655DRF-4832 DRF-4158 LY-465608 KT6-207 LSN-862 PPARalpha Agonist (mech)Fenofibrate Gemfibrozil Clofibrate Ciprofibrate Benzafibrate K-111LY518674 (LY674) KRP-101 NS-220 GW-9578 GW-7647 GW-9820 LF-200337ST-1929 Wy-14643 PPARdelta Agonist (mech) GW501516 GW-1514 L-165041 GW8547 PPARalpha/delta Dual GW-2433 Agonist (mech) PPARgamma/delta DualAgonist (mech) PPARalpha/gamma/delta CLX-0940 Modulator (mech) RXRAgonist (mech) Insulin Secretagogue Exanatide injectable (mech), GLP-1analogue (class) Exanatide LAR injectable Exanantide oral LiraglutideGLP-1 agonist (mech) exenatide (AC2993) liraglutide (NN2211) LY-307161CJC-113 ZP10 GLP-1 BIM-51077 DPPIV Inhibitor (mech) LAF-237 P32/98P93/01 NVP-728 Lipase Inhibitor (mech) Orlistat ATL962 GlucokinaseActivator Ro 28-1675 (mech) Ro 27-4375 beta-3 Agonist (mech) LY-337604L-796568 CP-331684 CP-331679 CP-114271 Rafabegron (TAK-677) YM-178 N5984GW427353 IBAT Inhibitor (mech) AZD-7806 SC-990 SC-017 GW-264 HM74a/HM74Agonist Acipimox (mech) Glucocorticoid A348441 Antagonist (mech) A362947CP394531 CP409069 CP472555 Glycogen Phosphorylase a NN4201 Inhibitor(mech) Ingliforib (CP368296) FXR Antagonist (mech) GW-4064 LXR Agonist(mech) GW-3965 T-0901317 T-0314407 FXR Antagonist (mech) GLP-1 Analogue(class) Albugon GSK-3beta Inhibitor (mech) PTP-1b Inhibitor (mech)ISIS-113715 KP102 Amylin Receptor Agonist Pramlintide (symlin/amylin) NOScavenger (mech) NOX-700 11beta-Hydroxysteroid BVT-3498 DehydrogenaseInhibitor Peptide YY hormone AC162325 Glucagon Antagonist NN-2501 (mech)PEPCK Inhibitor (mech) R1438 Somatotropin Release- SOM230 inhibitingFactor (mech) CPT-1 Inhibitor (mech) ST1326 Carboxypeptidase MLN-4760Inhibitor (mech) Leptin analogue (class) MetrileptinE. Combinations

The invention features a combination therapy comprising administering aglucose reabsorption inhibitor, such as an SGLT inhibitor, and one ormore antidiabetic agents) for the treatment of diabetes or Syndrome X,or associated symptoms or complications thereof. The demonstratedefficacy of SGLT inhibitors in numerous models of NIDDM validates theutility of this drug alone for the treatment of NIDDM in humans. Sinceglucose reabsorption inhibitors have a mechanism of action distinct fromthat of RXR modulators, the disclosed combination with RXR modulatorshas the advantage of reducing the amount of either drug necessary toachieve combined therapeutic or pharmaceutical efficacy, relative to theuse of either drug alone, thereby reducing one or more adverseside-effects, which often include weight gain, edema, cardiachypertrophy, hepatohypertrophy, hypoglycemia, or hepatotoxicity, or anycombination thereof.

The invention provides a method for treating diabetes or Syndrome X, orcomplications thereof in a subject, said method comprising administeringto said subject a jointly effective amount of a glucose reabsorptioninhibitor in combination with a jointly effective amount of one or moreantidiabetic agentsr. In one aspect of the invention, the antidiabeticagent is an RXR agonist or antagonist that increases insulin sensitivityin the subject. Methods to determine the insulin sensitizing activity ofan agent are well known in the art. For example, an insulin sensitizercan increase glucose tolerance in a subject in an oral glucose tolerancetest.

Particularly, the diabetes or Syndrome X, or associated symptoms orcomplication thereof is selected from IDDM, NIDDM, IGT, and IFG.

This invention also provides a pharmaceutical composition comprising oneor more glucose reabsorption inhibitors, one or more RXR modulators, anda pharmaceutically acceptable carrier. In one aspect of the invention,the RXR modulator is an RXR agonist that increases insulin sensitivityin the subject. In another aspect of the invention, the RXR modulator isan RXR antagonist that increases insulin sensitivity in the subject.

In particular, the glucose reabsorption inhibitor is a SGLT1 and/orSGLT2 inhibitor.

For use in medicine, the salt or salts of the compounds of Formula II orV refer to non-toxic “pharmaceutically acceptable salt or salts.” Othersalts may, however, be useful in the preparation of compounds accordingto this invention or of their pharmaceutically acceptable salts.Representative organic or inorganic acids include, but are not limitedto, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric,phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic,fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic,hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representativebasic/cationic salts include, but are not limited to, benzathine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine,procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, orzinc. The compounds of Formula II or a pharmaceutically acceptable saltthereof, may include an intramolecular salt thereof, or a solvate orhydrate thereof.

F. Administration, Formulation, and Dosages

The utility of the disclosed compounds, compositions, and combinationsto treat disorders in glucose and lipid metabolism can be determinedaccording to the procedures well known in the art (see the referenceslisted below), as well as all the procedures described in U.S. Pat. Nos.5,424,406, 5,731,292, 5,767,094, 5,830,873, 6,048,842, WO01/16123, andWO01/16122 which are incorporated herein by reference. The compound maybe administered to a patient by any conventional route ofadministration, including, but not limited to, intravenous, oral,subcutaneous, intramuscular, intradermal and parenteral administration.Preferably, formulations are for oral administration.

The present invention also provides pharmaceutical compositionscomprising one or more glucose reabsorption inhibitors of the inventionand one or more antidiabetic agents in association with apharmaceutically acceptable carrier.

The daily dosage of the products may be varied over a wide range from 1to 1000 mg per adult human per day. For oral administration, thecompositions are preferably provided in the form of tablets containing,0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,200, 250 or 500 milligrams of the active ingredient for the symptomaticadjustment of the dosage to the patient to be treated. The compounds maybe administered on a regimen of 1 to 2 times per day. The dosages,however, may be varied depending upon the requirement of the patients,the severity of the condition being treated and the compound beingemployed. The use of either daily administration or post-periodic dosingmay be employed. Preferably these compositions are in unit dosage formssuch as tablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, auto-injector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient oringredients are mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of one ormore disclosed glucose reabsorption inhibitors and one or moreantidiabetic agents, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient or ingredients are dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective dosage forms such as tablets, pillsand capsules. This solid preformulation composition is then subdividedinto unit dosage forms of the type described above containing from 0.1to about 500 mg of the active ingredient or ingredients of the presentinvention. The tablets or pills of the novel composition can be coatedor otherwise compounded to provide a dosage form affording the advantageof prolonged action. For example, the tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of material can be used for suchenteric layers or coatings, such materials including a number ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin. The liquid forms insuitably flavored suspending or dispersing agents may also include thesynthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

Advantageously, the combinations of one or more glucose reabsorptioninhibitors and one or more antidiabetic agents of the present inventionmay be administered in a single daily dose, or the total daily dosagemay be administered in divided doses of two, three or four times daily.Furthermore, one or more glucose reabsorption inhibitors and/or one ormore additional antidiabetic agents according to the present inventioncan be administered in intranasal form via topical use of suitableintranasal vehicles, or via transdermal skin patches well known to thoseof ordinary skill in that art. To be administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and/the like.

Wherein the present invention is directed to the administration of acombination, the compounds may be co-administered simultaneously,sequentially, or in a single pharmaceutical composition. Where thecompounds are administered separately, the number of dosages of eachcompound given per day, may not necessarily be the same, e.g. where onecompound may have a greater duration of activity, and will therefore, beadministered less frequently.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, thestrength of the preparation, the mode of administration, and theadvancement of the disease condition. In addition, factors associatedwith the particular patient being treated, including patient age,weight, diet and time of administration, will result in the need toadjust dosages.

The novel compositions of the present invention can also be administeredin the form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of lipids, including but notlimited to amphipathic lipids such as phosphatidylcholines,sphingomyelins, phosphatidylethanolamines, phophatidylcholines,cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphatidicacids, phosphatidylinositols, diacyl trimethylammonium propanes, diacyldimethylammonium propanes, and stearylamine, neutral lipids such astriglycerides, and combinations thereof. They may either containcholesterol or may be cholesterol-free.

From Formula (II) and other disclosed formulae it is evident that somecompounds in the compositions of the invention may have one or moreasymmetric carbon atoms in their structure. It is intended that thepresent invention include within its scope the stereochemically pureisomeric forms of the compounds as well as their racemates.Stereochemically pure isomeric forms may be obtained by the applicationof art known principles. Diastereoisomers may be separated by physicalseparation methods such as fractional crystallization andchromatographic techniques, and enantiomers may be separated from eachother by the selective crystallization of the diastereomeric salts withoptically active acids or bases or by chiral chromatography. Purestereoisomers may also be prepared synthetically from appropriatestereochemically pure starting materials, or by using stereospecificreactions.

Some compounds in the compositions of the present invention may havevarious individual isomers, such as trans and cis, and various alpha andbeta attachments (below and above the plane of the drawing). Inaddition, where the processes for the preparation of the compoundsaccording to the invention give rise to mixture of stereoisomers, theseisomers may be separated by conventional techniques such as preparativechromatography. The compounds may be prepared as a single stereoisomeror in racemic form as a mixture of some possible stereoisomers. Thenon-racemic forms may be obtained by either synthesis or resolution. Thecompounds may, for example, be resolved into their componentsenantiomers by standard techniques, such as the formation ofdiastereomeric pairs by salt formation. The compounds may also beresolved by covalent linkage to a chiral auxiliary, followed bychromatographic separation and/or crystallographic separation, andremoval of the chiral auxiliary. Alternatively, the compounds may beresolved using chiral chromatography. Unless otherwise noted, the scopeof the present invention is intended to cover all such isomers orstereoisomers per se, as well as mixtures of cis and trans isomers,mixtures of diastereomers and racemic mixtures of enantiomers (opticalisomers) as well.

The therapeutic effect of the glucose reabsorption inhibitoradministered alone or in combination with one or more additionalantidiabetic agent(s) in treating diabetes, Syndrome X, or associatedsymptoms or complications can be shown by methods known in the art. Thefollowing examples of synthesis and combination treatment with SGLTinhibitors and antidiabetic agents are intended to illustrate theinvention but not to limit it.

G. SYNTHETIC CHEMICAL EXAMPLES

The invention features substituted indazoles of formula(II) as describedabove in the Summary section, the description, and the appended claims.These disclosed compounds may be made according to traditional syntheticorganic chemistry methods or according to matrix or combinatorialchemistry methods. The Schemes and the Examples below provide generalguidance.

¹HNMR spectra were measured on a Brucker AC-300 (300 MHz) spectrometerusing tetramethylsilane (TMS) as an internal standard.

Example 1

2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}β-D-glucopyranoside

A. 1-(2,6-Bis-benzyloxy-4-methyl-phenyl)-ethanone: A mixture of1-(2,6-dihydroxy-4-methyl-phenyl)-ethanone (0.83 g, 5.0 mmol, Tsujiharaet. al. Med. Chem. 1999, 42, 5311), benzyl bromide (3.42 g, 20 mmol) andpotassium carbonate (6.9 g, 50 mmol) in DMF (15 mL) was stirred at 80°C. for 3 h. The mixture was filtered and the filtrate was diluted withethyl acetate. The organic layer was washed with water and brine, driedover anhydrous sodium sulfate and concentrated in vacuo. The residue wascrystallized from ether/hexane to afford the titled compound (1.56 g,90%) as an off-white solid.

B.1-(2,6-Bis-benzyloxy-4-methyl-phenyl)-3-(2,3-dihydro-benzofuran-5-yl)-propenone:To a suspension of Part A (1.56 g, 4.5 mmol) in 20 mL of ethanol wasadded powdered potassium hydroxide (0.5 g, 9 mmol), and the mixture wasstirred at room temperature for 10 min.2,3-Dihydro-benzofuran-5-carbaldehyde (1.66 g, 11 mmol) was added, andthe mixture was stirred at room temperature. When TLC showed noremaining ketone (48 h), water was added to quench the reaction. Theprecipitated solid was collected by filtration, washed with water, driedand recrystallized from ethanol/ether to give the titled compound (1.80g, 84%) as yellow crystals.

C.3-(2,3-Dihydro-benzofuran-5-yl)-1-(2,6-dihydroxy-4-methyl-phenyl)-propan-1-one:A solution of Part C (1.80 g, 3.78 mmol) in ethanol (20 mL) and ethylacetate (20 mL) was hydrogenated over 10% Pd—C (0.5 g) under H2 (40 psi)for 4 h. The catalyst was removed by filtration and the filtrate wasconcentrated in vacuo. The residue was crystallized from ether/hexane togive the titled compound (1.11 g, 98%) as a white solid.

D. 3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-1H-indazol-4-ol:To a solution of Part C (0.30 g, 1 mmol) in ethylene glycol (2 mL) wasadded hydrazine (0.064 g, 2 mmol). The reaction mixture was stirred for20 min at room temperature, then heated to 160° C. for 2 h. The solutionwas allowed to cool to room temperature, and it was poured into water(10 mL). The pH was adjusted to pH 7 by addition of acetic acid, and themixture was extracted with ethyl acetate. The organics were washed withbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The residue was crystallized from ether/hexane to give the titledcompound (0.19 g, 65%) as an off-white solid.

E.2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-1H-indazol4-yloxy}β-D-glucopyranoside and2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-6-O-acetyl-β-D-glucopyranoside:To a solution of Part D (0.15 g, 0.5 mmol) in acetone (1 mL) was addedpotassium carbonate (0.35 g, 2.5 mmol), followed by addition of2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide (0.41 g, 1 mmol). Thereaction mixture was stirred at room temperature for 24 h. Then solidswere filtered and washed with ethyl acetate. The ethyl acetate solutionwas washed with water and brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was dissolved in methanol (2 mL) andchloroform (0.5 mL), followed by addition of excess of potassiumcarbonate. The resulting mixture was stirred at room temperatureovernight. Then solids were filtered and washed with ethyl acetate. Theethyl acetate solution was washed with water and brine, dried overanhydrous sodium sulfate and concentrated in vacuo. The product waspurified by chromatography on silica gel: eluting withmethanol/chloroform (5:100) to give the title compound (0.010 g, yield:4%, by-product) as an off-white solid; eluting with methanol/chloroform(10:100) to give the title compound (0.096 g, yield: 42%) as a whitesolid. ¹HNMR (300 MHz, CD₃OD) δ 7.11 (s, 1H), 6.95 (d, J=8.23 Hz, 1H),6.86 (s, 1H), 6.61–6.58 (m, 2H), 5.22 (d, J=7.66 Hz, 1H), 4.48 (t,J=8.69 Hz, 2H), 3.95–3.90 (m, 1H), 3.74–3.68 (m, 1H), 3.64–3.59 (m, 1H),3.55–49 (m, 2H), 3.45–3.36 (m, 2H), 3.21–3.13 (m, 3H), 3.03–2.97 (m,2H), 2.43 (s, 3H). MS: m/z (MH⁺) 457.

Example 2

2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-6-O-acetyl-β-D-glucopyranoside

The title compound was isolated as a by-product in Example 1, Part E.¹HNMR (300 MHz, CD₃OD) δ 7.08 (s, 1H), 6.95–6.92 (m, 1H), 6.87 (s, 1H),6.58 (d, J=6.67 Hz, 2H), 5.19 (d, J=7.66 Hz, 1H), 4.46 (t, J=8.67 Hz,2H), 4.43–4.38 (m, 1H), 4.23–4.18 (m, 1H), 3.69–3.58 (m, 2H), 3.54–3.42(m, 3H), 3.16–3.11 (m, 3H), 3.01–2.96 (m, 2H), 2.42 (s, 3H), 1.93 (s,3H). MS: m/z (MH⁺) 499.

Example 3

2-{3-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}β-D-glucopyranoside

The title compound was prepared from1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone and2,3-dihydro-benzo[1,4]dioxine-6-carbaldehyde by the same procedure asdescribed in Example 1. ¹HNMR (300 MHz, CD₃OD) δ 6.85 (s, 1H), 6.71–6.67(m, 3H), 6.59 (s, 1H), 5.20 (d, J=7.51 Hz, 1H), 4.17 (s, 4H), 4.12–4.07,(m, 1H), 3.93–3.88 (m, 1H), 3.72–3.66 (m, 1H), 3.62–3.56 (m, 1H),3.52–3.47 (m, 2H), 3.41–3.36 (m, 1H), 3.22–3.16 (m, 1H), 2.98–2.9 (m,2H), 2.41 (s, 3H). MS: m/z (MH⁺) 473.

Example 4

2-[6-Methyl-3-(2-naphthalen-2-yl-ethyl)-1H-indazol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone and 2-Naphthaldehyde bythe same procedure as described in Example 1. ¹HNMR (400 MHz, CD₃OD) δ7.78 (m, 3H), 7.72 (s, 1H), 7.45–7.39 (m, 3H), 6.89 (s, 1H), 6.65 (s,1H), 5.27 (d, J=7.9 Hz, 1H), 3.93 (d, J=10.0 Hz, 1H), 3.76–3.66 (m, 2H),3.58–3.53 (m, 4H), 3.48–3.32 (m, 3H), 2.45 (s, 3H). MS: m/z (MH⁺) 465.

Example 5

2-{6-Methyl-3-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-1H-indazol-4-yloxy}-β-D-glucopyranoside

The intermediate, 1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone, wastreated with 2-naphthaldehyde as described in Example 1, Part B.Subsequent catalytic hydrogenation as described in Example 1, Part C,provided1-(2,6-Dihydroxy-4-methyl-phenyl)-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1-oneas a by-product. Further treatment of this by-product as described inExample 1, Part D and E, afforded the title compound. ¹HNMR (400 MHz,CD₃OD) δ 7.02 (s, 1H), 6.93 (m, 2H), 6.87 (s, 1H) 6.61 (s, 1H), 5.24 (d,J=7.73 Hz, 1H), 3.94 (d, J=12.05 Hz, 1H), 3.75–3.34 (m, 5H), 3.25–2.72(m, 8H), 2.43 (s, 3H), 1.81–1.77 (m, 4H). MS: m/z (MH⁺) 469.

Example 6

2-{3-[2-(6-Methoxy-naphthalen-2-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside

The title compound was prepared from1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone and6-methoxynaphthalene-2-carbaldehyde by the same procedure as describedin Example 1. ¹HNMR (300 MHz, CD₃COCD₃) δ 7.75–7.7(m, 3H), 7.5–7.45(1H),7.25–7.2(m, 1H), 6.9(s, 1H), 6.6(s, 1H), 5.77(d, J=7 Hz, 1H), 3.89(s,3H), 3.75–3.7(m, 2H), 3.65–3.55(m, 3H), 3.5–3.1(m, 4H), 2.39(s, 3H). MS:m/z (MH⁺) 495.

Example 7

2-{3-[2-(6-Methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}β-D-glucopyranoside

Intermediate 1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone, was treatedwith 6-methoxynaphthalene-2-carbaldehyde as described in Example 1, PartB. Subsequent catalytic hydrogenation as described in Example 1, Part C,provided 1-(2,6-dihydroxy-4-methyl-phenyl)-3-(6-methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-propan-1-one as a by-product. Furthertreatment of this by-product as described in Example 1, Part D and E,afforded the title compound. ¹HNMR (300 MHz, CD₃COCD₃) δ 7.2–7.0(m, 2H),6.95–6.85(m 3H), 6.6(s, 1H), 5.6(s, 1H), 5.27(d, J=7 Hz, 1H),3.95–3.85(m, 1H), 3.75–3.55(m, 6H), 3.37(s, 3H), 3.3–3.2(m, 1H),3.1–2.6(m, 8H), 2.05(s, 3H). MS: m/z (MH⁺) 499.

Example 8

2-{3-[2-(6-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside

Intermediate 1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone, was treatedwith 6-methoxynaphthalene-2-carbaldehyde as described in Part B ofExample 1. Subsequent catalytic hydrogenation as described in Part C ofExample 1 provided1-(2,6-dihydroxy-4-methyl-phenyl)-3-(6-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propan-1-oneas a by-product. Further treatment of this by-product as described inExample 1, Parts D and E, afforded the title compound. ¹HNMR (300 MHZ,CD₃COCD₃) δ 11.5(br s, 1H), 7.05–6.95(m, 1H), 6.87(s, 1H), 6.65–6.6(m,2H), 6.57(s, 1H), 5.21(d, J=7Hz, 1H), 4.5–2.25(m, 2H), 3.95–3.85(m, 1H),3.72(s, 3H), 3.7–3.55(m, 6H), 3.3–3.05(m, 2H), 3.0–2.75(m, 3H), 2.37(s,3H), 1.95–1.7(m, 2H), 1.5–1.35(m, 1H). MS: m/z (MH⁺) 499.

Example 9

2-{3-[2-(4-Methoxy-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}β-D-glucopyranoside

The title compound was prepared from1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone and4-methoxy-benzaldehyde by the same procedure as described in Example 1.¹HNMR (300 MHz, CD₃OD) δ 7.18 (s, 1H), 7.15 (s, 1H), 6.86(s, 1H), 6.82(s, 1H), 6.80 (s, 1H), 6.61 (s, 1H), 5.23 (d, J=7.78 Hz, 1H), 3.92(dd,J=1.79, 10.04 Hz, 1H), 3.75(s, 3H), 3.72–3.35(m, 6H), 3.25–3.15(m, 1H),3.10–2.94(m, 2H), 2.43(s, 3H). MS: m/z (MH⁺) 445.

Example 10

2-{3-[2-(4-Ethoxy-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}β-D-glucopyranoside

The title compound was prepared from1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone and 4-ethoxy-benzaldehydeby the same procedure as described in Example 1. ¹HNMR (300 MHz, CD₃OD)δ7.16 (s, 1H), 7.14 (s, 1H), 6.86 (s, 1H), 6.81 (s, 1H), 6.78 (s, 1H),6.61 (s, 1H), 5.23 (d, J=7.67 Hz, 1H), 3.99 (q, J=7.10, 7.01 Hz, 2H),3.95–3.90 (m, 1H), 3.72 (dd, J=5.62, 6.42 Hz, 1H), 3.65–3.35 (m, 7H),3.25–3.15 (m, 1H), 3.10–2.96 (m, 2H), 2.53 (s, 3H), 1.36 (t, J=6.96 Hz,3H). MS: m/z (MH⁺) 459.

Example 11

2-{3-[2-(4-Chloro-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside

The title compound was prepared from1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone and 4-chlorobenzaldehydeby the same procedure as described in Example 1. ¹HNMR (300 MHz, CD₃OD)δ 7.22 (s, 4H), 6.86 (s, 1H), 6.62 (s, 1H), 5.23 (d, J=7.48 Hz, 1H),3.93 (dd, J=1.95, 10.16 Hz, 1H), 3.72 (dd, J=5.69, 6.40 Hz, 1H),3.64–3.35 (m, 6H), 3.26–3.03 (m, 3H), 2.43 (s, 3H). MS: m/z (MH⁺) 449.

Example 12

2-{3-[2-(4-Trifluoromethyl-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}β-D-glucopyranoside

The title compound was prepared from1-(2,6-bis-benzyloxy-4-methyl-phenyl)-ethanone and4-trifluoromethyl-benzaldehyde by the same procedure as described inExample 1. ¹HNMR (400 MHz, CD₃OD) δ 7.56 (d, J=8.09 Hz, 2H), 7.45 (d,J=8.09 Hz, 2H), 6.90 (s, 1H), 6.66 (s, 1H), 5.26(d, J=7.7 Hz, 1H), 3.95(d, J=10.09 Hz, 1H), 3.75 (m, 1H), 3.63–3.45 (m, 5H), 3.31–3.20 (m, 3H),2.44 (s, 3H). MS: m/z (MH⁺) 483.

Example 13

2-[3-(2-Benzofuran-5-yl-ethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside

A. 1-(2-Hydroxy-6-methoxymethoxy-4-methyl-phenyl)-ethanone: A mixture of1-(2,6-dihydroxy-4-methyl-phenyl)-ethanone (11.65 g, 70 mmol),bromomethyl methyl ether (17.5 g, 140 mmol) and potassium carbonate (48g, 350 mmol) in acetonitrile (280 mL) was stirred at room temperatureovernight. The mixture was filtered and the filtrate was diluted withethyl acetate. The organic layer was washed with water and brine, driedover anhydrous sodium sulfate and concentrated in vacuo. The crudeproduct was purified by chromatography on silica gel eluting with ethylacetate/hexane (10:100) to yield the title compound (13.1 g, yield: 89%)as yellow oil.

B.3-Benzofuran-5-yl-1-(2-hydroxy-6-methoxymethoxy-4-methyl-phenyl)-propan-1-one:A 50% aqueous potassium hydroxide solution (6 mL) was added to asolution of Part A (1.26 g, 6 mmol) in ethanol (30 mL), and the mixturewas stirred at room temperature for 10 min. Then5-benzofurancarboxaldehyde (0.95 g, 6.5 mmol, Humphrey, Guy R., U.S.Pat. No. 5,149,838, 1992) was added, and the mixture was stirred at roomtemperature overnight. 4-(Dimethylamino)pyridine (0.73 g, 6 mmol) wasadded to the reaction mixture containing the chalcone, and the mixturewas hydrogenated over 10% Pd—C (0.35 g) under 30 psi for 4 h. Thecatalysts were removed by filtration, the filtrate was neutralized with10% aqueous HCl and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over anhydrous sodium sulfate andconcentrated in vacuo. The residue was crystallized from ethanol to givethe titled compound (1.23 g, 60%) as a white solid.

C. 3-Benzofuran-5-yl-1-(2,6-dihydroxy-4-methyl-phenyl)-propan-1-one: Toa solution of Part B (1.23 g, 3.6 mmol) in dioxane (12 mL) andisopropanol (6 mL) was added dropwise concentrated HCl (1.5 mL). Thereaction mixture was stirred at room temperature for 4 h, quenched withwater and extracted with ethyl acetate. The organic extracts were washedwith brine, dried over anhydrous sodium sulfate and concentrated invacuo. The crude product was purified by chromatography on silica geleluting with ethyl acetate/hexane (50:50) to give the titled compound(0.46 g, yield: 46%) as a yellow solid.

D.2-[3-(2-Benzofuran-5-yl-ethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside:The title compounds were prepared from Part C by the same procedure asdescribed in Example 1, Part D and E. ¹HNMR (300 MHz, CD₃OD) δ 7.69 (d,J=1.98 Hz, 1H), 7.51 (s, 1H), 7.37 (d, J=8.62 Hz, 1H), 7.22 (dd, J=1.23,8.35 Hz, 1H), 6.89 (s, 1H), 6.79–6.78 (m, 1H), 6.65 (s, 1H), 5.26 (d,J=7.67 Hz, 1H), 3.97–3.93 (m, 1H), 3.76–3.64 (m, 2H), 3.62–3.52 (m, 3H),3.50–3.43 (m, 2H), 3.27–3.17 (m, 2H), 2.46 (s, 3H). MS: m/z (MH⁺) 455.

Example 14

2-[3-(2-Benzofuran-5-yl-ethyl)-6-methyl-1H-indazol4-yloxy]-6-O-acetyl-β-D-glucopyran

The title compound was isolated as a by-product in Example 13, Part D.¹HNMR (300 MHz, CD₃OD) δ 7.66 (d, J=2.38 Hz, 1H), 7.48 (s, 1H), 7.37 (d,J=8.28 Hz, 1H), 7.20 (d, J=8.45 Hz, 1H), 6.90 (s, 1H), 6.77–6.75 (m,1H), 6.60 (s, 1H), 5.23 (d, J=7.76 Hz, 1H), 4.45–4.40 (m, 1H), 4.25–4.19(m, 1H), 3.75–3.63 (m, 2H), 3.59–3.42 (m, 3H), 3.25–3.15 (m, 3H), 2.45(s, 3H), 1.93 (s, 3H). MS: m/z (MH⁺) 497.

Example 15

2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1,6-dimethyl-1H-indazol-4-yloxy}-β-D-glucopyranoside

A.3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1,6-dimethyl-1H-indazol-4-ol:To a solution of3-(2,3-dihydro-benzofuran-5-yl)-1-(2,6-dihydroxy-4-methyl-phenyl)-propan-1-one(0.30 g, 1 mmol, prepared as the same procedure in Example 1, Part C) inethylene glycol (2 mL) was added methyl hydrazine (0.092 g, 2 mmol). Thereaction mixture was stirred for 20 min at room temperature, then heatedto 160° C. for 2 h. The solution was allowed to cool to roomtemperature, and it was poured into water (50 mL). The pH was adjustedto 7 by addition of acetic acid, and the mixture was extracted withethyl acetate. The organics were washed with brine, dried over anhydroussodium sulfate and concentrated in vacuo. The residue was crystallizedfrom ether/hexane to give the titled compound (0.12 g, 40%) as anoff-white solid.

B.2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1,6-dimethyl-1H-indazol-4-yloxy}-β-D-glucopyranoside:The title compound was prepared from Part D by the same proceduredescribed in Example 1, Part E. ¹HNMR (300 MHz, CD₃OD) δ 7.10 (s, 1H),6.94 (d, J=8.09 Hz, 1H), 6.85 (s, 1H), 6.85–6.61 (m 1H), 6.58 (s, 1H),5.22 (d, J=7.64 Hz, 1H), 4.48 (t, J=8.69 Hz, 2H), 3.92 (dd, J=2.08, 9.98Hz, 1H), 3.86 (s, 1H), 3.71 (dd, J=5.6888, 6.34 Hz, 1H), 3.64–3.38 (m,6H), 3.34–3.30 (m, 1H), 3.21–3.04 (m, 3H), 3.01–2.93 (m, 2H), 2.45(s,3H). MS: m/z (MH⁺) 471.

Example 16

2-{3-[2-(4-Methanesulfonylamino-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}β-D-glucopyranoside

A. 3-(4-Amino-phenyl)-1-(2,6-bis-benzyloxy-4-methyl-phenyl)-propenone: Amixture of 1-(2,6-bisbenzyloxy-4-methyl-phenyl)-ethanone (1.2 g, 3.5mmol), prepared as described in Part A of Example 1, and powderedpotassium hydroxide (0.4 g, 6.9 mmol) in ethanol (20 mL) was treated asdescribed in Part B of Example 1 to provide the product as a solid. Thesolids (1.1 g, 2.24 mmol) were suspended in methanol (25 mL) and treatedwith concentrated hydrochloric acid (1.5 mL). The mixture was stirred atreflux for forty minutes, cooled to room temperature (RT) and asaturated sodium bicarbonate solution was slowly added. The methanol wasremoved under reduced pressure and the aqueous mixture extracted withethyl acetate (2×60 mL). The combined ethyl acetate extract was washedwith brine, dried over MgSO₄, filtered and concentrated in vacuo toafford the title compound as a semi-solid (0.892 g, 89%).

B.N-{4-[3-(2,6-Bis-benzyloxy-4-methyl-phenyl)-3-oxo-propenyl]-phenyl}-methanesulfonamide:Methanesulfonyl chloride (0.16 mL, 2.1 mmol) was added dropwise to acold (0° C.) mixture of the compound prepared in Part A andtriethylamine (0.69 mL, 5 mmol) in methylene chloride (30 mL). Theresulting homogenous mixture was stirred at 0° C. for one hour thenwarmed up to RT. After an addition thirty minutes at RT ice water (30mL) was added and the layers separated. The organic extract was washedwith 0.5 M HCl solution (1×30 mL) then H₂O (1×30 mL) and dried overMgSO₄. The mixture was filtered and concentrated in vacuo to provide thetitle compound (0.98 g, 94%).

C.2-{3-[2-(4-Methanesulfonylamino-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}β-D-glucopyranoside: The compound prepared in Part B was treated asdescribed in Example 1, Parts C, D and E, to provide the title compoundas an off-white solid. ¹HNMR (300 MHz, CD₃OD) δ 7.23 (d, J=8.48 Hz, 2H),7.13 (d, J=8.36 Hz, 2H), 6.86 (s, 1H), 6.61 (s, 1H), 7.20 (d, J=7.51 Hz,1H), 3.95–3.91 (m, 1H), 3.74–3.37 (m, 5H), 3.26–3.05 (m, 4H), 2.90 (s,3H), 2.43 (s, 3H). MS: m/z (MH⁺) 508.

Example 17

2-[3-(2-Cyclohexyl-ethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside

A. 1-(2,6-Bis-benzyloxy-4-methyl-phenyl)-3-cyclohex-1-enyl-propenone:Lithium diisopropylamide (1.5 mL, 1.5 mmol, 2M solution inheptane/tetrahydrofuran/ethylbenzene) was slowly added to a cold (−78°C.) solution of 1-(2,6-Bis-benzyloxy-4-methyl-phenyl)-ethanone preparedin Part A of Example 1 in dry THF (10 mL). The mixture was stirred at−78° C. with slow warming to 0° C. over a 60 minute period thenre-cooled to −30° C. and 1-cylcohexene-1-carboxaldehyde (256 mg, 2.3mmol) was added dropwise. After three hours at room temperature, themixture was cooled in an ice bath and quenched with saturated ammoniumchloride (5 mL). Water (50 mL) was added and the mixture extracted withethyl acetate (2×60 mL). The combined ethyl acetate extracts was washedwith brine, dried over MgSO₄, filtered, evaporated in vacuo and purifiedby column chromatography to provide the title compound (0.166 g, 51%based on recovered starting material).

B. 3-Cyclohexyl-1-(2,6-dihydroxy-4-methyl-phenyl)-propan-1-one: Asolution of the compound (0.16 g, 0.37 mmol) prepared in Part A in amixture of ethanol and ethyl acetate (1:1) was hydrogenated over acatalytic amount of 10% Pd—C in a Parr apparatus at 15 psi of hydrogenpressure for 24 hours. The mixture was filtered through CELITE™ andevaporated in vacuo to afford the title compound (0.093 g, 97%).

C.2-[3-(2-Cyclohexyl-ethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside:The compound obtained in Part B was treated as described in Example 1,Part D and E, to provide the title compound as an off-white solid. ¹HNMR(400 MHz, CD₃OD) δ 6.85 (s, 1H), 6.58 (s, 1H), 5.2 (d, J=7.36 Hz, 1H),3.92 (d, J=11.91 Hz, 1H), 3.69–3 (m, 1H), 3.49–3.60 (m, 2H), 3.38–3.43(m, 1H), 3.18–3.20 (m, 1H), 2.96–2.98 (m, 1H), 2.43 (s, 3H), 1.82–1.88(m, 2H), 1.61–1.74 (m, 6H), 1.33–1.35 (m, 5H), 1.24-1.30 (m, 2H). MS:m/z (MH⁺) 421.

Example 18

2-[3-(2-Benzofuran-5-yl-ethyl)-1H-indazol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from 1-(2,6-dihydroxy-phenyl)-ethanoneand 5-benzofuran carboxaldehyde by the same procedure as described inExample 13. ¹HNMR (300 MHz, CD₃OD) δ 7.67 (d, J=2.2 Hz, 1H), 7.49 (s,1H), 7.37 (d, J=8.42 Hz, 1H), 7.29 (d, J=8.11 Hz, 1H), 7.25–7.19 (m,1H), 7.08 (d, J=8.3 Hz, 1H), 6.78–6.75 (m, 2H), 5.26 (d, J=7.71 Hz, 1H),3.92 (dd, J=11.79, 1.88 Hz, 1H), 3.75–3.63 (m, 1H), 3.62–3.54 (m, 3H),3.53–3.45 (m, 3H), 3.26–3.18 (m, 2H). MS: m/z (MH⁺) 441.

Example 19

2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-ethyl-1H-indazol-4-yloxy}β-D-glucopyranoside

A. 1-(2,6-Dihydroxy-4-ethyl-phenyl)-ethanone: A solution of1,3-diacetoxyacetophenone (3.2 g, 13.5 mmol) in acetic acid (30 mL) washydrogenated over 10% Pd—C (3.0 g) under H₂ (50 psi) overnight. Thecatalyst was removed by filtration and the filtrate was concentrated invacuo. The resulting crude product (1,3-diacetoxy-5-ethylbenzene) wasused directly in the next step.

To a suspension of AlCl₃ (5.4 g, 40.6 mmol) in chlorobenzene (15 mL) wasadded dropwise a solution of 1,3-diacetoxy-5-ethylbenzene (3.0 g, 13.5mmol) at 90° C. over the period of 30 min. The reaction mixture wasstirred at 90° C. for 1 h and then poured into ice-10% HCl (50 mL pleaseclarify). The aqueous layer was extracted with ethyl acetate. Theorganic layer was washed with water and brine, dried over anhydroussodium sulfate and concentrated in vacuo. The residue was crystallizedfrom ether/hexane to give the title compound (1.5 g, 62%) as a whitesolid.

B.2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-ethyl-1H-indazol-4-yloxy}β-D-glucopyranoside: The title compound was prepared from Part A and2,3-dihydro-benzofuran-5-carbaldehyde by the same procedure as describedin Example 1. ¹HNMR (300 MHz, CD₃OD) δ 7.10 (s, 1H), 6.95 (d, J=7.90 Hz,1H), 6.88 (s, 1H), 6.64 (s, 1H), 6.60 (d, J=8.11 Hz, 1H), 5.24 (d,J=7.38 Hz, 1H), 4.48 (t, J=8.69 Hz, 2H), 3.93 (dd, J=1.92, 9.97 Hz, 1H),3.72 (dd, J=5.75, 6.58 Hz, 1H), 3.66–3.35 (m, 6H), 3.25–3.19 (m, 1H),3.15 (t, J=8.62 Hz, 2H), 3.08–2.92 (m, 2H), 2.72 (q, J=7.54, 7.57 Hz,2H), 1.29 (t, J=7;47 Hz, 3H). MS: m/z (MH⁺) 471.

Example 20

2-[3-(4-Methoxy-phenylsulfanylmethyl)-1H-indazol-4-yloxy]-β-D-glucopyranoside

A.1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-methyl-indazol-1-yl]-ethanone:To a solution of 4-(tert-Butyl-dimethylsilanyloxy)-3-methyl-1H-indazole(200 mg, 0.76 mmol), prepared according to Boehm et. al. J. Med. Chem.,2000, 43, 2664–2674, in DMF (3 mL) at room temperature was addedpotassium carbonate (516 mg, 3.80 mmol) followed by acetic anhydride(143 □l, 1.52 mmol) and the resulting reaction mixture was allowed tostir at room temperature for 2 h. The reaction mixture was poured ontowater and extracted with ethyl acetate. The combined ethyl acetateextracts were dried over anhydrous sodium sulfate and concentrated invacuo. Chromatography (SiO₂, 20% Ethyl Acetate-Hexanes eluant) provided200 mg of the desired product as an off-white solid. (231 mg, 87%yield).

B.1-[3-Bromomethyl-4-(tert-butyl-dimethyl-silanyoxy)-indazol-1-yl]-ethanone:To a solution of the acetyl compound prepared in the previous step (1.9g, 6.25 mmol), in carbon tetrachloride at room temperature was addedAIBN (205 mg, 1.25 mmol) and NBS (1.45 g, 8.13 mmol). The resultingreaction mixture was allowed to stir at reflux for 1 h then cooled toroom temperature and stirred for an additional 18 h. The reactionmixture was concentrated in vacuo. Chromatography (SiO₂, 5% EthylAcetate-Hexanes eluant) provided the desired bromide as dark red oil inquantitative yields.

C.1-[4-(tert-Butyl-dimethyl-silanyloxy)-3-(4-methoxy-phenylsulfanylmethyl)-indazol-1-yl]-ethanone:To a solution of the bromide prepared in the previous step (0.2 g, 0.522mmol), in methylene chloride at room temperature was added triethylamine(0.055 g, 0.548 mmol) and 4-methoxy-benzenethiol (0.077 g, 0.548 mmol)and the resulting mixture was stirred at room temperature for 4 h. Thereaction mixture was diluted with methylene chloride and washed withwater, brine, dried over magnesium sulfate, filtered and concentrated invacuo. Chromatography (SiO₂, 5% ethyl acetate:hexane eluent) provided0.2 g of the desired product as an off-white solid (0.23 g, 85% yield).

D.1-[4-Hydroxy-3-(4-methoxy-phenylsulfanylmethyl)-indazol-1-yl]-ethanone:To a solution of the compound prepared in part C (0.2 g, 0.452 mmol), inDMF at room temperature was added potassium fluoride (0.053 g, 0.905mmol) and 48% aqueous hydrogen bromide (0.03 mL, 0.136 mmol) and theresulting mixture was allowed to stir at room temperature for 5 days.The reaction solution was poured into a saturated sodium bicarbonatesolution and extracted with ethyl acetate/hexane (3:1). The combinedethyl acetate extracts were washed with water, brine, dried over MgSO₄,filtered and concentrated in vacuo. Chromatography (SiO₂, 10% ethylacetate:hexane eluent) provided the title compound (0.076 g, 50%) as anoff-white solid.

E.2-[1-Acetyl-3-(4-methoxy-phenylsulfanylmethyl)-1H-indazol-4-yloxy]-β-D-glucopyranoside:To a solution of the hydroxyl compound prepared in part D (0.076 g,0.244 mmol) in acetone at room temperature was added potassium carbonate(0.085 g, 0.61 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosylbromide (0.15 g, 0.366 mmol) and the resulting mixture was allowed tostir at room temperature 24 h. The reaction mixture was diluted withwater, the acetone was removed and the product was extracted with ethylacetate. The combined ethyl acetate extracts were washed with brine,dried over MgSO₄, filtered and concentrated in vacuo. Chromatography(SiO₂, 25% ethyl acetate:hexane eluent) provided the acetylatedintermediate (0.065 g, 40%) as an off-white solid. To a solution of thisintermediate (0.065 g, 0.099 mmol) in methanol at room temperature wasadded sodium methoxide in methanol (0.1 mL, 0.463 mmol) and theresulting reaction mixture was allowed to stir at room temperature for 1h. The reaction mixture was diluted with water, the methanol was removedand the product was extracted with ethyl acetate. The combined ethylacetate extracts were washed with brine, dried over MgSO₄, filtered andconcentrated in vacuo to yield the title compound (0.036 g, 80%) as anoff-white solid. ¹HNMR (300 MHz, CD₃OD) δ 7.30–7.25 (m, 3H), 7.07 (d,J=8.27 Hz, 1H), 6.83–6.76 (m, 3H), 5.15 (d, J=7.55 Hz, 1H), 4.61 (d, Hz,J=13.0 Hz, 1H), 4.41 (d, J=13.0 Hz, 1H), 3.96–3.91 (dd, J=1.95 Hz,J=10.05 Hz, 1H), 3.75 (s, 3H), 3.63–3.45 (m, 5H). MS: m/z (MH⁺) 449.

Example 21

2-[3-(4-Methoxy-benzyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside

A. 1-(2,6-Dihydroxy-4-methyl-phenyl)-2-(4-methoxy-phenyl)-ethanone(NB18926–186): To a mixture of 5-methyl-benzene-1,3-diol (0.37 g, 3mmol) and (4-methoxy-phenyl)-acetic acid (0.55 g, 3 mmol) was addeddropwise boron trifluoride diethyl etherate (1.5 mL, 12 mmol). Thereaction mixture was heated to 100° C. and stirred for 2 h. Aftercooling to room temperature, the mixture poured into aqueous sodiumacetate and stirred for 5 min, then extracted with ethyl acetate. Theorganic extracts were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo. The crude product was purified by chromatographyon silica gel: eluting with acetone/ethyl acetate/hexane (12:4:100) toprovide the titled compound (0.24 g, 29%) as a yellow solid; elutingwith acetone/ethyl acetate/hexane (15:5:100) to provide1-(2,4-dihydroxy-6-methyl-phenyl)-2-(4-methoxy-phenyl)-ethanone (0.48 g,59%) as a yellow solid.

B.2-[3-(4-Methoxy-benzyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside:the title compound was prepared from Part A by the same procedure asdescribed in Example 1, Part D and Part E. ¹HNMR (300 MHz, CD₃OD) δ 7.22(d, J=8.69 Hz, 1H), 6.87 (s, 1H), 6.78 (d, J=8.57 Hz, 2H), 6.58 (s, 1H),5.12 (d, J=7.64 Hz, 1H), 4.49 (d, J=15.12 Hz, 1H), 4.24 (d, J=15.06 Hz,1H), 3.89 (dd, J=2.07, 12.06 Hz, 1H). 3.73 (s, 3H), 3.70–3.62 (m, 2H),3.58–3.45 (m, 2H), 3.39 (d, J=8.71 Hz, 1H), 2.41 (s, 3H). MS: m/z (MH⁺)431.

Example 22

2-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside

The title compound was prepared from 5-methyl-benzene-1,3-diol and(2,3-Dihydro-benzofuran-5-yl)-acetic acid by the same procedure asdescribed in Example 16. ¹HNMR (300 MHz, CD₃OD) δ 7.16 (s, 1H), 7.03 (d,J=7.80 Hz, 1H), 6.86 (s, 1H), 6.59–6.56 (m, 2H), 5.12 (d, J=7.47 Hz,1H), 4.48–4.43 (m, 3H), 4.23 (d, J=15.07 Hz, 1H), 3.90(dd, J=1.63, 12.03Hz, 1H), 3.70–3.59 (m, 2H), 2.57–3.51 (m, 2H), 3.48–3.35 (m, 1H), 3.11(d, J=8.73 Hz, 2H), 2.41 (s, 3H). MS: m/z (MH⁺) 443.

H. BIOLOGICAL EXAMPLES Example 1 Materials and Methods

Cloning of the human SGLT1 and human SGLT2 cDNAs and construction of themammalian expression vector: The human SGLT1 cDNA (Genbank M24847) wascloned from human small intestine. Human SGLT2 cDNA (Genbank M95549) wascloned from human kidney. Both full cDNAs were subcloned into pcDNA andsequenced to verify the integrity of the construct.

Generation of CHO-K1 cells stably expressing human SGLT1 or human SGLT2:Transfection of CHO-K1 cells was performed using DMRIE-C reagent (LifeTechnologies, Gaithersburg, Md.). Transfectants were then selected inthe presence of the antibiotic G418 (Gibco-BRL, Grand Island, N.Y.) at400 μg/ml. Individual clones were then characterized using thefunctional assay described below.

Cell-based assay for sodium-dependent glucose transport: Cell linesstably expressing human SGLT1 or SGLT2 were then used for functionalanalysis of Na+-dependent glucose uptake. Briefly, cells were plated ata density of 65,000 cells per well in a 96-well plate and allowed togrow for 48 hours. Cells were subsequently washed one time with AssayBuffer (50 mM HEPES pH 7.4, 20 mM Tris, 5 mM KCl, 1 mM MgCl₂, 1 mM CaCl₂and 137 mM NaCl) and treated with compound in the absence or presence ofNaCl for 15 minutes. Cells were then labeled with¹⁴C-α-methylglucopyranoside (AMG, Sigma, St. Louis, Mo.), anon-metabolizable glucose analog specific for sodium-dependent glucosetransporters as previously described (Peng, H. and Lever J. E.Post-transcriptional regulation of Na⁺/glucose cotransporter (SGLT1)gene expression in LLC-PK1 cells. J Biol Chem 1995;270:20536–20542.).After 2 hours the labelled cells were washed three times with ice-coldPBS. After aspiration, cells were solubilized using Microscint 20(Packard, Meriden, Conn.) and Na-dependent ¹⁴C-AMG uptake was quantifiedby measuring radioactivity. Plates were counted in a TopCount (Packard,Meriden, Conn.). Results are reported as the % inhibition or IC50 valuefrom a representative experiment. Variability for the functional assaywas typically within 20%.

Example 2 In Vivo Assay for Efficacy

Male Zucker Diabetic Fatty (ZDF) rats (7–8 weeks) were obtained fromCharles River. Animals were maintained on a 12-hour light/dark cycle ina temperature-controlled room. Animals were given ad libitum access tofood (standard rodent diet Purina 5008) and water. Animals were fastedfor 12 hours prior to initiation of the experiment. On the morning ofthe experiment, animals were administered vehicle (0.5% methylcellulose)or compound by oral gavage (1 ml/kg). After one hour, animals receivedan oral glucose challenge (4 ml/kg of 50% solution) and were immediatelyplaced in metabolism cages. Animals were given free access to water andurine was collected for 4 hours. Urinary glucose was quantified usingthe Trinder Reagent (Sigma).

Example 3 Effects on Plasma Glucose, Plasma Insulin, PlasmaTriglycerides, Plasma Free Fatty Acids, Liver Weight, and Body Weight

To examine the effect of an SGLT inhibitor in combination with an RXRagonist, female db/db mice (6–7 weeks of age/Jackson Labs, ME) aretreated daily for 11 days with vehicle (0.5% methylcellulose), an RXRagonist (0.1–10 mpk (mg/kg)), T-1095 (100 mpk), or RXR agonist plus SGLTinhibitor. Mice (n=8 animals/group) receive the test compounds orvehicle by oral gavage in a volume of 10 ml/kg of body weight. Bodyweight is recorded on day 1, prior to dosing, and days 4, 8 and 11.Eighteen hours after the final dose, mice are weighed and anesthetizedwith CO₂/O₂ (70:30). Mice are then bled by retro-orbital sinus punctureinto 2 mL heparinized polypropylene tubes on ice. Plasma samples arethen assayed for glucose, insulin, triglycerides, and free fatty acids.Livers are excised, weighed and frozen.

The SGLT inhibitors and RXR agonists have distinct mechanisms of action.Improved glycemic control, measured as a decrease in plasma glucose,plasma insulin, plasma free fatty acids, or plasma triglycerides, or acombination thereof, can be observed at lower concentrations of an RXRagonist when given in combination with an SGLT inhibitor. Therefore, aleftward shift in the dose-response curve for effect of an RXR agoniston the above parameters can become apparent. In addition, the weightgain observed following treatment with RXR agonists is less pronouncedwhen given with the SGLT inhibitor, since SGLT inhibitors' promotion ofthe urinary excretion of glucose and loss of calories from the body isdemonstrated by reduction in weight or weight gain. Also, since SGLTinhibitors promote a mild diuresis, the edema (and the edematous weightgain) commonly observed after treatment with RXR agonists can be lesspronounced or absent. A reduction in the amount of an RXR agonistnecessary to achieve efficacy in turn improves the side-effect profile.The decreased side effects can include such conditions as fatty liver,increased liver weight, body weight gain, heart weight gain, edema,cardiac hypertrophy, hepatohypertrophy, hypoglycemia, andhepatotoxicity, or any combination thereof.

Example 4 Effects on plasma Glucose, HbA1c, Hematocrit, Plasma Insulin,Plasma Triglycerides, Plasma Free Fatty Acids, Total Cholesterol, HDL,Plasma Drug Levels, Liver Weight, Heart Weight, Fat Content and BodyWeight

To examine the effect of an SGLT inhibitor in combination with an RXRagonist, male ZDF rats (6 weeks of age/GMI) are treated daily for 28days with vehicle (0.5% methylcellulose), an RXR agonist (0.1 mpk–10mpk), SGLT inhibitor (3–100 mpk), or RXR agonist plus SGLT inhibitor.Rats (n=8 animals/group) receive the test compounds or vehicle by oralgavage in a volume of 2 ml/kg of body weight. Body weight is recorded onday 1, prior to dosing, and twice a week for the duration of the study.On the day prior to the final dose, animals are fasted overnight. Onehour after the final dose, rats are weighed and anesthetized with CO₂/O₂(70:30). Rats are then bled by retro-orbital sinus puncture into 2 mLheparinized polypropylene tubes on ice. Rats then receive a glucosechallenge (2 g/kg p.o) and are placed in metabolism cages for the urinecollection (4 hours). Animals are then sacrificed and epididymal fatpads, livers, and hearts are excised, weighed and frozen forhistological examination. Plasma samples are then assayed for glucose,HbA1c, insulin, hematocrit, plasma drug levels, total cholesterol, HDL,free fatty acids, and triglycerides. Urine volume and urinary glucose,protein, osmolarity, electrolytes (Na, K, Cl), BUN and creatinine aremeasured.

The SGLT inhibitors and other antidiabetic agents, such as RXR agonists,have distinct mechanisms of action. Improved glycemic control, measuredas a decrease in plasma glucose, HbA1c, plasma insulin, or plasmatriglycerides, or a combination thereof, can be observed at lowerconcentrations of RXR agonists when given in combination with an SGLTinhibitor. Therefore, a leftward shift in the dose-response curve foreffect of RXR agonists on the above parameters can become apparent. Inaddition, the weight gain observed following treatment with RXR agonistsis less pronounced when given with the SGLT inhibitor, since SGLTinhibitors' promotion of the urinary excretion of glucose and loss ofcalories from the body is demonstrated by reduction in weight or weightgain. Also, since SGLT inhibitors promote a mild diuresis, the edema(and the edematous weight gain) commonly observed after treatment withRXR agonists can be less pronounced or absent. This can be demonstratedby a reduction in the RXR agonist-induced increase in heart weight. Areduction in the amount of RXR agonists necessary to achieve efficacy inturn improves the side-effect profile. The decreased side effects caninclude such conditions as fatty liver, increased liver weight, bodyweight gain, heart weight gain, edema, cardiac hypertrophy,hepatohypertrophy, hypoglycemia, and hepatotoxicity, or any combinationthereof.

The above examples can also show that the oral administration of an SGLTinhibitor in combination with an antidiabetic agent, such as an RXRmodulator, may improve the status of other markers of diabetes mellitusincluding glycosylated hemoglobin (Hgb A1C) levels. Particularly, theoral administration of an SGLT inhibitor in combination with one or moreantidiabetic agents can reduce body weight or body weight gain as wellas liver weight or liver weight gain, compared to administration of oneor antidiabetic agents alone.

Thus, for treating diabetes, particularly Type II diabetes mellitus, orSyndrome X, a compound of Formula (II) in combination with one or moreantidiabetic agents, such as RXR agonists or antagonists that increaseinsulin sensitivity, may be employed comprising administering repeatedoral doses of the compound of formula I in the range of about 25 to 1000mg once or twice daily and repeated doses of the anti-diabetic agent oragents at jointly effective dosages. The jointly effective dosage forantidiabetic agents disclosed herein may be readily determined by thoseskilled in the art based on standard dosage guidelines. In particular,such combined administration can be effective to accomplish reduction ofbody weight, body weight gain, liver weight, or liver weight gain in thesubject.

Additionally, a method comprising (a) administering to a subject ajointly effective amount of a glucose reabsorption inhibitor; and (b)administering to the subject a jointly effective amount of anantidiabetic agent, such as an RXR modulator, can be used to reduce bodyweight, body weight gain, or liver weight of the subject in needthereof, wherein the combined administration can be in any order and thecombined jointly effective amounts provide the desired therapeuticeffect.

Also, a method comprising (a) administering to a subject a jointlyeffective amount of a glucose reabsorption inhibitor; and (b)administering to the subject a jointly effective amount of anantidiabetic agent, such as an RXR modulator, can be used to controlbody weight, body weight gain, liver weight, or liver weight gain of thesubject having diabetes, Syndrome X, or associated symptoms orcomplications, wherein the combined administration can be in any orderand the combined jointly effective amounts providing the desiredtherapeutic effect.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, the strength of the preparation and theadvancement of the disease condition. In addition, factors associatedwith the particular patient being treated, including patient's sex, age,weight, diet, time of administration and concomitant diseases, willresult in the need to adjust dosages.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

TABLE 3 CHOK-SGLT1 CHOK-SGLT2 Example # % Inh (10 uM) IC50 (uM) ± SEM  148 0.458 ± 0.061 19 inactive 0.532 ± 0.047 13 52 0.491 ± 0.056 15 470.754 ± 0.069 18 43  1.2 ± 0.071 21 inactive 0.959 ± 0.118  6  7 1*  3inactive  1.59 ± 0.025 10  5  2.0 ± 0.071 14 42  1.5 ± 0.071  5 inactive 3.25 ± 0.461  4 18  1.95 ± 0.816  9 11  3.05 ± 0.319  8 inactive 67%Inh. @ 10 μM  2 14 69% Inh. @ 10 μM 11 12 66% Inh. @ 10 μM 20 38 64%Inh. @ 10 μM 17 inactive 67% Inh. @ 10 μM  7 inactive 43% Inh. @ 10 μM22 inactive 40% Inh. @ 10 μM 12 inactive 36% Inh. @ 10 μM 16 inactive42% Inh. @ 10 μM *tested once only.

1. A compound of formula(II):

wherein R¹ is H or C₁₋₄ alkyl; R² is H, F, Cl, methoxy, or C₁₋₃ alkyl; Qis —(CH₂)_(n)— where n=0, 1, or 2; or, where R² is H, F, Cl, or methoxy,then Q can also be selected from —CH₂—S—; Z is substituted orunsubstituted, and is selected from C₃₋₇ cycloalkyl, phenyl, benzhydryl,5- or 6-membered heteroaryl having 1 or 2 heteroatoms independentlyselected from N, O, and S, a biaryl, and a 9- or 10-membered fusedbicyclyl or fused heterobicyclyl, wherein each fused heterobicyclyl hasbetween 1 and 4 heteroatoms independently selected from. N, O, and S;P=H or acetyl; or a pharmaceutically acceptable salt thereof.
 2. Acompound of claim 1, wherein R¹ is H.
 3. A compound of claim 1, whereinR² is H, methyl, or ethyl.
 4. A compound of claim 1, wherein Q is—(CH₂)_(n)— and n is 1 or
 2. 5. A compound of claim 1, wherein Z isindependently substituted with between 1 and 3 substituentsindependently selected from C₁₋₄ alkoxy, C₁₋₄ alkyl, C₃₋₆ cycloalkyl,halo, hydroxy, cyano, amino, C₁₋₄ alkylthio, C₁₋₄ aminoalkyl, mono- anddi(C₁₋₄ alkyl)amino, phenyl, 5–6 membered heterocyclyl containingbetween 1 and 3 heteroatoms independently selected from N, S, and O; andwherein the substituent(s) on Z can be further independently substitutedwith between 1 and 3 substituents independently selected from C₁₋₄alkoxy, C₁₋₄ alkyl, halo, hydroxy, cyano, amino, C₁₋₄ alkylthio,phenoxy, —CONR^(a)R^(b), —NHSO₂R^(a), and —SO₂NR^(a)R^(b) where each ofR^(a) and R^(b) is independently selected from H and C₁₋₄ alkyl.
 6. Acompound of claim 1, wherein Z is phenyl, cyclopentyl, cyclohexyl,4-substituted cyclohexyl, 2- or 3-substituted cyclopentyl, 4-substitutedphenyl, 3,4-disubstituted phenyl, substituted thiophenyl, thiophenyl,biaryl, benzofuranyl, dihydrobenzofuranyl, 4-substituted pyridyl,benzo[b]thienyl, benzothiophenyl, indanyl, naphthyl,5,6,7,8-tetrahydronapthyl, 1,2,3,4-tetrahydronaphthyl, or benzo[1,4]dioxan.
 7. A compound of claim 5, wherein Z is unsubstituted orsubstituted with between 1 and 2 substituents independently selectedfrom methoxy, ethoxy, fluoro, chloro, methyl, ethyl, propyl, isopropyl,cyclopropyl, and phenyl.
 8. A compound of claim 1, wherein Z isbiphenyl, 4-ethylphenyl, (4-propyl)phenyl, 4-methoxyphenyl,4-ethoxyphenyl, 4-methylthiophenyl, benzofuran-5-yl,dihydrobenzofuran-5-yl, naphthyl, or dihydrobenzofuran-6-yl, or(5-ethylthio)phenyl.
 9. A compound of claim 1 wherein R¹ is H; and R² isH, methyl, ethyl, propyl, or isopropyl.
 10. A compound of claim 1,wherein Q is —(CH₂)_(n)—; n is 1 or 2; and R² is H, methyl, or ethyl.11. A compound of claim 10, wherein R¹ is methyl.
 12. A compound ofclaim 2, wherein R² is H, methyl, or ethyl; wherein Q is —(CH₂)_(n)— andn is 1 or 2; Z is phenyl, cyclopentyl, cyclohexyl, 4-substitutedcyclohexyl, 2- or 3-substituted cyclopentyl, 4-substituted phenyl,3,4-disubstituted phenyl, substituted thiophene, thiophenyl, biaryl,benzofuranyl, dihydrobenzofuranyl, 4-substituted pyridyl,benzo[b]thienyl, benzothiophenyl, indanyl, naphthyl,5,6,7,8-tetrahydronapthyl, 1,2,3,4-tetrahydronaphthyl, or benzo[1,4]dioxan; and wherein Z is unsubstituted or substituted with between 1 and2 substituents independently selected from methoxy, ethoxy, fluoro,chloro, methyl, ethyl, propyl, isopropyl, cyclopropyl, and phenyl.
 13. Acompound of claim 1, wherein R² is H, methyl, or ethyl; wherein Q is—(CH₂)_(n)— and n is 1 or 2; and Z is biphenyl, 4-ethylphenyl,(4-propyl)phenyl, 4-methoxyphenyl, 4-ethoxyphenyl, 4-methylthiophenyl,benzofuran-5-yl, dihydrobenzofuran-5-yl, naphthyl, ordihydrobenzofuran-6-yl, or (5-ethylthio)phenyl.
 14. A compound of claim1, selected from2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-[3-(2-Benzofuran-5-yl-ethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-1,6-dimethyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-ethyl-1H-indazol-4-yloxy}-β-D-glucopyranosideand2-[3-(4-Methoxy-benzyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside.15. A compound of claim 1, selected from2-[3-(2-Benzofuran-5-yl-ethyl)-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(6-Methoxy-naphthalen-2-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-ethyl]-6-methyl-1H-indazol4-yloxy}-β-D-glucopyranoside;2-{3-[2-(4-Ethoxy-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-{6-Methyl-3-[2-(5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-[6-Methyl-3-(2-naphthalen-2-yl-ethyl)-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(4-Methoxy-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(6-Methoxy-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranosideand2-[3-(2-Benzofuran-5-yl-ethyl)-6-methyl-1H-indazol-4-yloxy]-6-O-acetyl-β-D-glucopyranoside.16. A compound of claim 1, selected from2-{3-[2-(6-Methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(4-Chloro-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside:2-[3-(4-Methoxy-phenylsulfanylmethyl)-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[3-(2-Cyclohexyl-ethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[3-(2,3-Dihydro-benzofuran-5-ylmethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-{3-[2-(4-Trifluoromethyl-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranoside;2-{3-[2-(4-Methanesulfonylamino-phenyl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-β-D-glucopyranosideand2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}-6-O-acetyl-β-D-glucopyranoside.17. A compound of claim 1, selected from2-[3-(4-Ethyl-benzyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[6-Methyl-3-(4-propyl-benzyl)-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Methylsulfanyl-benzyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Biphenyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Cyclopropyl-benzyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranosideand2-[3-(5-Ethylthiophen-2-ylmethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside.18. A compound of claim 1, selected from2-{3-[2-(2,3-Dihydro-benzofuran-5-yl)-ethyl]-6-methyl-1H-indazol-4-yloxy}β-D-glucopyranoside;2-[3-(2-Benzofuran-5-yl-ethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;2-[3-(4-Ethyl-benzyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside;and2-[3-(5-Ethylthiophen-2-ylmethyl)-6-methyl-1H-indazol-4-yloxy]-β-D-glucopyranoside.19. A pharmaceutical composition, comprising a compound of claim 1, 5,6, 11, 12, 14, 15, 16, 17, or 18 and a pharmaceutically acceptablecarrier.
 20. A pharmaceutical composition, comprising a compound ofclaim 14.